|
1
|
Kataki AD, Gupta PG, Cheema U, Nisbet A, Wang Y, Kocher HM, Pérez-Mancera PA, Velliou EG. Mapping Tumor-Stroma-ECM Interactions in Spatially Advanced 3D Models of Pancreatic Cancer. ACS APPLIED MATERIALS & INTERFACES 2025; 17:16708-16724. [PMID: 40052705 PMCID: PMC11931495 DOI: 10.1021/acsami.5c02296] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/03/2025] [Revised: 02/19/2025] [Accepted: 02/20/2025] [Indexed: 03/21/2025]
Abstract
Bioengineering-based in vitro tumor models are increasingly important as tools for studying disease progression and therapy response for many cancers, including the deadly pancreatic ductal adenocarcinoma (PDAC) that exhibits a tumor/tissue microenvironment of high cellular/biochemical complexity. Therefore, it is crucial for in vitro models to capture that complexity and to enable investigation of the interplay between cancer cells and factors such as extracellular matrix (ECM) proteins or stroma cells. Using polyurethane (PU) scaffolds, we performed a systematic study on how different ECM protein scaffold coatings impact the long-term cell evolution in scaffolds containing only cancer or only stroma cells (activated stellate and endothelial cells). To investigate potential further changes in those biomarkers due to cancer-stroma interactions, we mapped their expression in dual/zonal scaffolds consisting of a cancer core and a stroma periphery, spatially mimicking the fibrotic/desmoplastic reaction in PDAC. In our single scaffolds, we observed that the protein coating affected the cancer cell spatial aggregation, matrix deposition, and biomarker upregulation in a cell-line-dependent manner. In single stroma scaffolds, different levels of fibrosis/desmoplasia in terms of ECM composition/quantity were generated depending on the ECM coating. When studying the evolution of cancer and stroma cells in our dual/zonal model, biomarkers linked to cell aggressiveness/invasiveness were further upregulated by both cancer and stroma cells as compared to single scaffold models. Collectively, our study advances the understanding of how different ECM proteins impact the long-term cell evolution in PU scaffolds. Our findings show that within our bioengineered models, we can stimulate the cells of the PDAC microenvironment to develop different levels of aggressiveness/invasiveness, as well as different levels of fibrosis. Furthermore, we highlight the importance of considering spatial complexity to map cell invasion. Our work contributes to the design of in vitro models with variable, yet biomimetic, tissue-like properties for studying the tumor microenvironment's role in cancer progression.
Collapse
Affiliation(s)
- Anna-Dimitra Kataki
- Centre
for 3D models of Health and Disease, Division of Surgery and Interventional
Science, University College London, London W1W 7TY, U.K.
| | - Priyanka G. Gupta
- Centre
for 3D models of Health and Disease, Division of Surgery and Interventional
Science, University College London, London W1W 7TY, U.K.
- School
of Life and Health Sciences, Whitelands College, University of Roehampton, London SW15 4JD, U.K.
| | - Umber Cheema
- Centre
for 3D models of Health and Disease, Division of Surgery and Interventional
Science, University College London, London W1W 7TY, U.K.
| | - Andrew Nisbet
- Department
of Medical Physics and Biomedical Engineering, University College London, London WC1E 6BT, U.K.
| | - Yaohe Wang
- Centre
for Cancer Biomarkers and Biotherapeutics, Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, U.K.
| | - Hemant M. Kocher
- Centre
for Tumour Biology and Experimental Cancer Medicine, Barts Cancer
Institute, Queen Mary University of London, London EC1M 6BQ, U.K.
| | - Pedro A. Pérez-Mancera
- Department
of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool L69 3GE, U.K.
| | - Eirini G. Velliou
- Centre
for 3D models of Health and Disease, Division of Surgery and Interventional
Science, University College London, London W1W 7TY, U.K.
| |
Collapse
|
|
2
|
Firpo MA, Boucher KM, Bleicher J, Khanderao GD, Rosati A, Poruk KE, Kamal S, Marzullo L, De Marco M, Falco A, Genovese A, Adler JM, De Laurenzi V, Adler DG, Affolter KE, Garrido-Laguna I, Scaife CL, Turco MC, Mulvihill SJ. Multianalyte Serum Biomarker Panel for Early Detection of Pancreatic Adenocarcinoma. JCO Clin Cancer Inform 2023; 7:e2200160. [PMID: 36913644 PMCID: PMC10530881 DOI: 10.1200/cci.22.00160] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2022] [Revised: 01/10/2023] [Accepted: 02/03/2023] [Indexed: 03/14/2023] Open
Abstract
PURPOSE We determined whether a large, multianalyte panel of circulating biomarkers can improve detection of early-stage pancreatic ductal adenocarcinoma (PDAC). MATERIALS AND METHODS We defined a biologically relevant subspace of blood analytes on the basis of previous identification in premalignant lesions or early-stage PDAC and evaluated each in pilot studies. The 31 analytes that met minimum diagnostic accuracy were measured in serum of 837 subjects (461 healthy, 194 benign pancreatic disease, and 182 early-stage PDAC). We used machine learning to develop classification algorithms using the relationship between subjects on the basis of their changes across the predictors. Model performance was subsequently evaluated in an independent validation data set from 186 additional subjects. RESULTS A classification model was trained on 669 subjects (358 healthy, 159 benign, and 152 early-stage PDAC). Model evaluation on a hold-out test set of 168 subjects (103 healthy, 35 benign, and 30 early-stage PDAC) yielded an area under the receiver operating characteristic curve (AUC) of 0.920 for classification of PDAC from non-PDAC (benign and healthy controls) and an AUC of 0.944 for PDAC versus healthy controls. The algorithm was then validated in 146 subsequent cases presenting with pancreatic disease (73 benign pancreatic disease and 73 early- and late-stage PDAC cases) and 40 healthy control subjects. The validation set yielded an AUC of 0.919 for classification of PDAC from non-PDAC and an AUC of 0.925 for PDAC versus healthy controls. CONCLUSION Individually weak serum biomarkers can be combined into a strong classification algorithm to develop a blood test to identify patients who may benefit from further testing.
Collapse
Affiliation(s)
- Matthew A. Firpo
- Department of Surgery, School of Medicine, University of Utah, Salt Lake City, UT
| | - Kenneth M. Boucher
- Department of Oncological Sciences, School of Medicine, University of Utah, Salt Lake City, UT
| | - Josh Bleicher
- Department of Surgery, School of Medicine, University of Utah, Salt Lake City, UT
| | - Gayatri D. Khanderao
- Department of Surgery, School of Medicine, University of Utah, Salt Lake City, UT
| | - Alessandra Rosati
- BIOUNIVERSA s.r.l., Baronissi, Italy
- Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana” University of Salerno, Baronissi, Italy
| | - Katherine E. Poruk
- Department of Surgery, School of Medicine, University of Utah, Salt Lake City, UT
| | - Sama Kamal
- Department of Surgery, School of Medicine, University of Utah, Salt Lake City, UT
| | - Liberato Marzullo
- BIOUNIVERSA s.r.l., Baronissi, Italy
- Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana” University of Salerno, Baronissi, Italy
| | - Margot De Marco
- BIOUNIVERSA s.r.l., Baronissi, Italy
- Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana” University of Salerno, Baronissi, Italy
| | - Antonia Falco
- BIOUNIVERSA s.r.l., Baronissi, Italy
- Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana” University of Salerno, Baronissi, Italy
| | - Armando Genovese
- University Hospital “San Giovanni di Dio e Ruggi D'Aragona,” Salerno, Italy
| | - Jessica M. Adler
- Department of Surgery, School of Medicine, University of Utah, Salt Lake City, UT
| | - Vincenzo De Laurenzi
- BIOUNIVERSA s.r.l., Baronissi, Italy
- Department of Medicine and Biotechnology, University G d'Annunzio and CeSI-MeT, Chieti, Italy
| | - Douglas G. Adler
- Department of Internal Medicine, School of Medicine, University of Utah, Salt Lake City, UT
| | - Kajsa E. Affolter
- Department of Pathology, School of Medicine, University of Utah, Salt Lake City, UT
| | - Ignacio Garrido-Laguna
- Department of Oncological Sciences, School of Medicine, University of Utah, Salt Lake City, UT
| | - Courtney L. Scaife
- Department of Surgery, School of Medicine, University of Utah, Salt Lake City, UT
| | - M. Caterina Turco
- BIOUNIVERSA s.r.l., Baronissi, Italy
- Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana” University of Salerno, Baronissi, Italy
| | - Sean J. Mulvihill
- Department of Surgery, School of Medicine, University of Utah, Salt Lake City, UT
| |
Collapse
|
|
3
|
Matsumura K, Hayashi H, Uemura N, Ogata Y, Zhao L, Sato H, Shiraishi Y, Kuroki H, Kitamura F, Kaida T, Higashi T, Nakagawa S, Mima K, Imai K, Yamashita YI, Baba H. Thrombospondin-1 overexpression stimulates loss of Smad4 and accelerates malignant behavior via TGF-β signal activation in pancreatic ductal adenocarcinoma. Transl Oncol 2022; 26:101533. [PMID: 36115074 PMCID: PMC9483797 DOI: 10.1016/j.tranon.2022.101533] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Revised: 09/03/2022] [Accepted: 09/05/2022] [Indexed: 11/22/2022] Open
Abstract
INTRODUCTION Pancreatic ductal adenocarcinoma (PDAC) is characterized by abundant stroma and cancer-associated fibroblasts (CAFs) provide a favorable tumor microenvironment. Smad4 is known as tumor suppressor in several types of cancers including PDAC, and loss of Smad4 triggers accelerated cell invasiveness and metastatic potential. The thrombospondin-1 (TSP-1) can act as a major activator of latent transforming growth factor-β (TGF-β) in vivo. However, the roles of TSP-1 and the mediator of Smad4 loss and TGF-β signal activation during PDAC progression have not yet been addressed. The aim is to elucidate the biological role of TSP-1 in PDAC progression. METHODS AND RESULTS High substrate stiffness stimulated TSP-1 expression in CAFs, and TSP-1 knockdown inhibited cell proliferation with suppressed profibrogenic and activated stroma-related gene expressions in CAFs. Paracrine TSP-1 treatment for PDAC cells promoted cell proliferation and epithelial mesenchymal transition (EMT) with activated TGF-β signals such as phosphorylated Akt and Smad2/3 expressions. Surprisingly, knockdown of DPC4 (Smad4 gene) induced TSP-1 overexpression with TGF-β signal activation in PDAC cells. Interestingly, TSP-1 overexpression also induced downregulation of Smad4 expression and enhanced cell proliferation in vitro and in vivo. Treatment with LSKL peptide, which antagonizes TSP-1-mediated latent TGF-β activation, attenuated cell proliferation, migration and chemoresistance with enhanced apoptosis in PDAC cells. CONCLUSIONS TSP-1 derived from CAFs stimulates loss of Smad4 expression in cancer cells and accelerates malignant behavior by TGF-β signal activation in PDAC. TSP-1 could be a novel therapeutic target, not only for CAFs in stiff stroma, but also for cancer cells in the PDAC microenvironment.
Collapse
Affiliation(s)
- Kazuki Matsumura
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556, Japan
| | - Hiromitsu Hayashi
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556, Japan
| | - Norio Uemura
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556, Japan
| | - Yoko Ogata
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556, Japan
| | - Liu Zhao
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556, Japan
| | - Hiroki Sato
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556, Japan
| | - Yuta Shiraishi
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556, Japan
| | - Hideyuki Kuroki
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556, Japan
| | - Fumimasa Kitamura
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556, Japan
| | - Takayoshi Kaida
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556, Japan
| | - Takaaki Higashi
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556, Japan
| | - Shigeki Nakagawa
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556, Japan
| | - Kosuke Mima
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556, Japan
| | - Katsunori Imai
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556, Japan
| | - Yo-Ichi Yamashita
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556, Japan
| | - Hideo Baba
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556, Japan.
| |
Collapse
|
|
4
|
Chen Z, Wei X, Dong S, Han F, He R, Zhou W. Challenges and Opportunities Associated With Platelets in Pancreatic Cancer. Front Oncol 2022; 12:850485. [PMID: 35494001 PMCID: PMC9039220 DOI: 10.3389/fonc.2022.850485] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2022] [Accepted: 03/15/2022] [Indexed: 01/02/2023] Open
Abstract
Pancreatic cancer is one of the most common malignant tumors in the digestive system with a poor prognosis. Accordingly, better understanding of the molecular mechanisms and innovative therapies are warranted to improve the prognosis of this patient population. In addition to playing a crucial role in coagulation, platelets reportedly contribute to the growth, invasion and metastasis of various tumors, including pancreatic cancer. This narrative review brings together currently available evidence on the impact of platelets on pancreatic cancer, including the platelet-related molecular mechanisms of cancer promotion, pancreatic cancer fibrosis, immune evasion, drug resistance mechanisms, thrombosis, targeted platelet therapy, combined radiotherapy and chemotherapy treatment, platelet combined with nanotechnology treatment and potential applications of pancreatic cancer organoids. A refined understanding of the role of platelets in pancreatic cancer provides the foothold for identifying new therapeutic targets.
Collapse
Affiliation(s)
- Zhou Chen
- The First Clinical Medical College, Lanzhou University, Lanzhou, China
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, China
| | - Xiaodong Wei
- Emergency Department, Gansu Provincial Hospital, Lanzhou, China
| | - Shi Dong
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, China
| | - Fangfang Han
- The First Clinical Medical College, Lanzhou University, Lanzhou, China
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, China
| | - Ru He
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, China
| | - Wence Zhou
- The First Clinical Medical College, Lanzhou University, Lanzhou, China
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, China
| |
Collapse
|
|
5
|
Jin A, Zhou J, Yu P, Zhou S, Chang C. High Expression of THBS1 Leads to a Poor Prognosis in Papillary Thyroid Cancer and Suppresses the Anti-Tumor Immune Microenvironment. Technol Cancer Res Treat 2022; 21:15330338221085360. [PMID: 35315710 PMCID: PMC8943644 DOI: 10.1177/15330338221085360] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
Abstract
Objectives: To study the role of thrombospondin-1 (THBS1) in
papillary thyroid cancer (PTC) prognosis and the immune microenvironment.
Methods: A retrospective cohort study was designed, and data
from The Cancer Genome Atlas database and PTC tissues from Fudan University
Shanghai Cancer Center were used. Weighted gene co-expression network analysis
was performed to build a THBS1-immune-related gene prognostic
index (T-I index). Results: High THBS1 expression
was correlated with advanced TNM stage, higher recurrence risk, and shorter
progression-free interval. High THBS1 expression correlated
with MAPK and PD1 pathways indicating a tumor promoting and immunity-inhibiting
tendency. The T-I index showed a powerful capacity to predict progression-free
survival and immunotherapy benefit. Conclusion: High expression of
THBS1 leads to a poor prognosis in PTCs and suppresses the
anti-tumor immune microenvironment.
Collapse
Affiliation(s)
- Anqi Jin
- 89667Fudan University Shanghai Cancer Center, Shanghai, China
| | - Jin Zhou
- 89667Fudan University Shanghai Cancer Center, Shanghai, China
| | - Pengcheng Yu
- 89667Fudan University Shanghai Cancer Center, Shanghai, China
| | - Shichong Zhou
- 89667Fudan University Shanghai Cancer Center, Shanghai, China
| | - Cai Chang
- 89667Fudan University Shanghai Cancer Center, Shanghai, China
| |
Collapse
|
|
6
|
Maneshi P, Mason J, Dongre M, Öhlund D. Targeting Tumor-Stromal Interactions in Pancreatic Cancer: Impact of Collagens and Mechanical Traits. Front Cell Dev Biol 2021; 9:787485. [PMID: 34901028 PMCID: PMC8656238 DOI: 10.3389/fcell.2021.787485] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Accepted: 11/01/2021] [Indexed: 01/18/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) has one of the worst outcomes among cancers with a 5-years survival rate of below 10%. This is a result of late diagnosis and the lack of effective treatments. The tumor is characterized by a highly fibrotic stroma containing distinct cellular components, embedded within an extracellular matrix (ECM). This ECM-abundant tumor microenvironment (TME) in PDAC plays a pivotal role in tumor progression and resistance to treatment. Cancer-associated fibroblasts (CAFs), being a dominant cell type of the stroma, are in fact functionally heterogeneous populations of cells within the TME. Certain subtypes of CAFs are the main producer of the ECM components of the stroma, with the most abundant one being the collagen family of proteins. Collagens are large macromolecules that upon deposition into the ECM form supramolecular fibrillar structures which provide a mechanical framework to the TME. They not only bring structure to the tissue by being the main structural proteins but also contain binding domains that interact with surface receptors on the cancer cells. These interactions can induce various responses in the cancer cells and activate signaling pathways leading to epithelial-to-mesenchymal transition (EMT) and ultimately metastasis. In addition, collagens are one of the main contributors to building up mechanical forces in the tumor. These forces influence the signaling pathways that are involved in cell motility and tumor progression and affect tumor microstructure and tissue stiffness by exerting solid stress and interstitial fluid pressure on the cells. Taken together, the TME is subjected to various types of mechanical forces and interactions that affect tumor progression, metastasis, and drug response. In this review article, we aim to summarize and contextualize the recent knowledge of components of the PDAC stroma, especially the role of different collagens and mechanical traits on tumor progression. We furthermore discuss different experimental models available for studying tumor-stromal interactions and finally discuss potential therapeutic targets within the stroma.
Collapse
Affiliation(s)
- Parniyan Maneshi
- Department of Radiation Sciences, Umeå University, Umeå, Sweden
- Wallenberg Centre for Molecular Medicine, Umeå University, Umeå, Sweden
| | - James Mason
- Department of Radiation Sciences, Umeå University, Umeå, Sweden
- Wallenberg Centre for Molecular Medicine, Umeå University, Umeå, Sweden
| | - Mitesh Dongre
- Department of Radiation Sciences, Umeå University, Umeå, Sweden
- Wallenberg Centre for Molecular Medicine, Umeå University, Umeå, Sweden
| | - Daniel Öhlund
- Department of Radiation Sciences, Umeå University, Umeå, Sweden
- Wallenberg Centre for Molecular Medicine, Umeå University, Umeå, Sweden
| |
Collapse
|
|
7
|
Targeting Ovarian Carcinoma with TSP-1:CD47 Antagonist TAX2 Activates Anti-Tumor Immunity. Cancers (Basel) 2021; 13:cancers13195019. [PMID: 34638503 PMCID: PMC8508526 DOI: 10.3390/cancers13195019] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Revised: 10/02/2021] [Accepted: 10/03/2021] [Indexed: 11/17/2022] Open
Abstract
TAX2 peptide is a cyclic peptide that acts as an orthosteric antagonist for thrombospondin-1 (TSP-1) interaction with CD47. TAX2 was first described for its anti-angiogenic activities and showed anti-cancer efficacy in numerous preclinical models. Here, we aimed at providing an extensive molecular characterization of TAX2 mode of action, while evaluating its potential in ovarian cancer therapy. Multidisciplinary approaches were used to qualify a TAX2 drug candidate in terms of stability, solubility and potency. Then, efficacy studies, together with benchmark experiments, were performed in relevant mouse models of ovarian carcinoma. TAX2 peptide appears to be stable and soluble in clinically relevant solvents, while displaying a favorable safety profile. Moreover, clinical data mining allowed for the identification of TSP-1 as a relevant pharmacological target in ovarian cancer. In mice, TAX2 therapy inhibits ovarian tumor growth and metastatic dissemination, while activating anti-cancer adaptive immunity. Interestingly, TAX2 also synergizes when administered in combination with anti-PD-1 immune checkpoint inhibitiors. Altogether, our data expose TAX2 as an optimized candidate with advanced preclinical characterization. Using relevant syngeneic ovarian carcinoma models, we highlighted TAX2's ability to convert poorly immunogenic tumors into ones displaying effective anti-tumor T-cell immunity.
Collapse
|
|
8
|
Benchmark of site- and structure-specific quantitative tissue N-glycoproteomics for discovery of potential N-glycoprotein markers: a case study of pancreatic cancer. Glycoconj J 2021; 38:213-231. [PMID: 33835347 DOI: 10.1007/s10719-021-09994-8] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2020] [Revised: 03/16/2021] [Accepted: 03/19/2021] [Indexed: 02/07/2023]
Abstract
Pancreatic cancer is a highly malignant tumor of the digestive tract that is difficult to diagnose and treat. It is more common in developed countries and has become one of the main causes of death in some countries and regions. Currently, pancreatic cancer generally has a poor prognosis, partly due to the lack of symptoms in the early stages of pancreatic cancer. Therefore, most cases are diagnosed at advanced stage. With the continuous in-depth research of glycoproteomics in precision medical diagnosis, there have been some reports on quantitative analysis of cancer-related cells, plasma or tissues to find specific biomarkers for targeted therapy. This research is based on the developed complete N-linked glycopeptide database search engine GPSeeker, combined with liquid-mass spectrometry and stable diethyl isotope labeling, providing a benchmark of site- and structure-specific quantitative tissue N-glycoproteomics for discovery of potential N-glycoprotein markers. With spectrum-level FDR ≤1%, 20,038 intact N-Glycopeptides corresponding to 4518 peptide backbones, 228 N-glycan monosaccharide compositions 1026 N-glycan putative structures, 4460 N-glycosites and 3437 intact N-glycoproteins were identified. With the criteria of ≥1.5-fold change and p value<0.05, 52 differentially expressed intact N-glycopeptides (DEGPs) were found in pancreatic cancer tussues relative to control, where 38 up-regulated and 14 down-regulated, respectively.
Collapse
|
|
9
|
Yang H, Zhou T, Sorenson CM, Sheibani N, Liu B. Myeloid-Derived TSP1 (Thrombospondin-1) Contributes to Abdominal Aortic Aneurysm Through Suppressing Tissue Inhibitor of Metalloproteinases-1. Arterioscler Thromb Vasc Biol 2020; 40:e350-e366. [PMID: 33028100 PMCID: PMC7686278 DOI: 10.1161/atvbaha.120.314913] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
OBJECTIVE Abdominal aortic aneurysm is characterized by the progressive loss of aortic integrity and accumulation of inflammatory cells primarily macrophages. We previously reported that global deletion of matricellular protein TSP1 (thrombospondin-1) protects mice from aneurysm formation. The objective of the current study is to investigate the cellular and molecular mechanisms underlying TSP1's action in aneurysm. Approach and Results: Using RNA fluorescent in situ hybridization, we identified macrophages being the major source of TSP1 in human and mouse aneurysmal tissues, accounting for over 70% of cells that actively expressed Thbs1 mRNA. Lack of TSP1 in macrophages decreased solution-based gelatinase activities by elevating TIMP1 (tissue inhibitor of metalloproteinases-1) without affecting the major MMPs (matrix metalloproteinases). Knocking down Timp1 restored the ability of Thbs1-/- macrophages to invade matrix. Finally, we generated Thbs1flox/flox mice and crossed them with Lyz2-cre mice. In the CaCl2-induced model of abdominal aortic aneurysm, lacking TSP1 in myeloid cells was sufficient to protect mice from aneurysm by reducing macrophage accumulation and preserving aortic integrity. CONCLUSIONS TSP1 contributes to aneurysm pathogenesis, at least in part, by suppressing TIMP1 expression, which subsequently enables inflammatory macrophages to infiltrate vascular tissues.
Collapse
MESH Headings
- Animals
- Aorta, Abdominal/metabolism
- Aorta, Abdominal/pathology
- Aortic Aneurysm, Abdominal/genetics
- Aortic Aneurysm, Abdominal/metabolism
- Aortic Aneurysm, Abdominal/pathology
- Cells, Cultured
- Dilatation, Pathologic
- Disease Models, Animal
- Down-Regulation
- Humans
- Macrophages/metabolism
- Macrophages/pathology
- Male
- Matrix Metalloproteinases/metabolism
- Mice, Inbred C57BL
- Mice, Knockout, ApoE
- Signal Transduction
- Thrombospondin 1/deficiency
- Thrombospondin 1/genetics
- Thrombospondin 1/metabolism
- Tissue Inhibitor of Metalloproteinase-1/genetics
- Tissue Inhibitor of Metalloproteinase-1/metabolism
Collapse
Affiliation(s)
- Huan Yang
- Department of Surgery,School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53705
| | - Ting Zhou
- Department of Surgery,School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53705
| | - Christine M. Sorenson
- Department of Ophthalmology and Visual Sciences, University of Wisconsin-Madison, Madison, WI 53705
| | - Nader Sheibani
- Department of Ophthalmology and Visual Sciences, University of Wisconsin-Madison, Madison, WI 53705
| | - Bo Liu
- Department of Surgery,School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53705
- Department of Cellular and Regenerative Biology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53705
| |
Collapse
|
|
10
|
Wang P, Zeng Z, Lin C, Wang J, Xu W, Ma W, Xiang Q, Liu H, Liu SL. Thrombospondin-1 as a Potential Therapeutic Target: Multiple Roles in Cancers. Curr Pharm Des 2020; 26:2116-2136. [PMID: 32003661 DOI: 10.2174/1381612826666200128091506] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2019] [Accepted: 01/27/2020] [Indexed: 01/16/2023]
Abstract
Thrombospondin-1, an extracellular matrix protein, is the first identified natural angiogenesis inhibitor. Thrombospondin-1 participates in a great number of physiological and pathological processes, including cell-cell and cell-matrix interactions via a number of cell receptors, including CD36 and CD47, which plays a vital role in mediating inflammation and performs a promoting effect in pulmonary arterial vasculopathy and diabetes. Thrombospondin-1 consists of six domains, which combine with different molecules and participate in various functions in cancers, serving as a critical member in diverse pathways in cancers. Thrombospondin-1 works as a cancer promotor in some pathways but as a cancer suppressor in others, which makes it highly possible that its erroneous functioning might lead to opposite effects. Therefore, subdividing the roles of thrombospondin-1 and distinguishing them in cancers are necessary. Complex structure and multiple roles take disadvantage of the research and application of thrombospondin-1. Compared with the whole thrombospondin-1 protein, each thrombospondin- 1 active peptide performs an uncomplicated structure and, nevertheless, a specific role. In other words, various thrombospondin-1 active peptides may function differently. For instance, thrombospondin-1 could both promote and inhibit glioblastoma, which is significantly inhibited by the three type I repeats, a thrombospondin-1 active peptide but promoted by the fragment 167-569, a thrombospondin-1 active peptide consisting of the procollagen homology domain and the three type I repeats. Further studies of the functions of thrombospondin-1 active peptides and applying them reasonably are necessary. In addition to mediating cancerogenesis, thrombospondin-1 is also affected by cancer development, as reflected by its expression in plasma and the cancer tissue. Therefore, thrombospondin-1 may be a potential biomarker for pre-clinical and clinical application. This review summarizes findings on the multiple roles of thrombospondin-1 in cancer processes, with a focus on its use as a potential therapeutic target.
Collapse
Affiliation(s)
- Pengfei Wang
- Genomics Research Center (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), College of Pharmacy, Harbin Medical University, Harbin, 150081, China.,HMU-UCCSM Centre for Infection and Genomics, Harbin, 150081, China.,Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Heilongjiang, China
| | - Zheng Zeng
- Genomics Research Center (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), College of Pharmacy, Harbin Medical University, Harbin, 150081, China.,HMU-UCCSM Centre for Infection and Genomics, Harbin, 150081, China.,Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Heilongjiang, China
| | - Caiji Lin
- Genomics Research Center (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), College of Pharmacy, Harbin Medical University, Harbin, 150081, China.,HMU-UCCSM Centre for Infection and Genomics, Harbin, 150081, China.,Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Heilongjiang, China
| | - Jiali Wang
- Genomics Research Center (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), College of Pharmacy, Harbin Medical University, Harbin, 150081, China.,HMU-UCCSM Centre for Infection and Genomics, Harbin, 150081, China.,Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Heilongjiang, China
| | - Wenwen Xu
- Genomics Research Center (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), College of Pharmacy, Harbin Medical University, Harbin, 150081, China.,HMU-UCCSM Centre for Infection and Genomics, Harbin, 150081, China.,Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Heilongjiang, China
| | - Wenqing Ma
- Genomics Research Center (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), College of Pharmacy, Harbin Medical University, Harbin, 150081, China.,HMU-UCCSM Centre for Infection and Genomics, Harbin, 150081, China.,Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Heilongjiang, China
| | - Qian Xiang
- Genomics Research Center (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), College of Pharmacy, Harbin Medical University, Harbin, 150081, China.,HMU-UCCSM Centre for Infection and Genomics, Harbin, 150081, China.,Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Heilongjiang, China
| | - Huidi Liu
- Genomics Research Center (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), College of Pharmacy, Harbin Medical University, Harbin, 150081, China.,HMU-UCCSM Centre for Infection and Genomics, Harbin, 150081, China.,Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Heilongjiang, China.,Arnie Charbonneau Cancer Institute, University of Calgary, Calgary, T2N 4N1, Canada.,Department of Microbiology, Immunology and Infectious Diseases, University of Calgary, Calgary, T2N 4N1, Canada
| | - Shu-Lin Liu
- Genomics Research Center (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), College of Pharmacy, Harbin Medical University, Harbin, 150081, China.,HMU-UCCSM Centre for Infection and Genomics, Harbin, 150081, China.,Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Heilongjiang, China.,Department of Microbiology, Immunology and Infectious Diseases, University of Calgary, Calgary, T2N 4N1, Canada
| |
Collapse
|
|
11
|
Lu W, Li N, Liao F. Identification of Key Genes and Pathways in Pancreatic Cancer Gene Expression Profile by Integrative Analysis. Genes (Basel) 2019; 10:genes10080612. [PMID: 31412643 PMCID: PMC6722756 DOI: 10.3390/genes10080612] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2019] [Revised: 07/31/2019] [Accepted: 08/07/2019] [Indexed: 12/15/2022] Open
Abstract
Background: Pancreatic cancer is one of the malignant tumors that threaten human health. Methods: The gene expression profiles of GSE15471, GSE19650, GSE32676 and GSE71989 were downloaded from the gene expression omnibus database including pancreatic cancer and normal samples. The differentially expressed genes between the two types of samples were identified with the Limma package using R language. The gene ontology functional and pathway enrichment analyses of differentially-expressed genes were performed by the DAVID software followed by the construction of a protein–protein interaction network. Hub gene identification was performed by the plug-in cytoHubba in cytoscape software, and the reliability and survival analysis of hub genes was carried out in The Cancer Genome Atlas gene expression data. Results: The 138 differentially expressed genes were significantly enriched in biological processes including cell migration, cell adhesion and several pathways, mainly associated with extracellular matrix-receptor interaction and focal adhesion pathway in pancreatic cancer. The top hub genes, namely thrombospondin 1, DNA topoisomerase II alpha, syndecan 1, maternal embryonic leucine zipper kinase and proto-oncogene receptor tyrosine kinase Met were identified from the protein–protein interaction network. The expression levels of hub genes were consistent with data obtained in The Cancer Genome Atlas. DNA topoisomerase II alpha, syndecan 1, maternal embryonic leucine zipper kinase and proto-oncogene receptor tyrosine kinase Met were significantly linked with poor survival in pancreatic adenocarcinoma. Conclusions: These hub genes may be used as potential targets for pancreatic cancer diagnosis and treatment.
Collapse
Affiliation(s)
- Wenzong Lu
- Department of Biomedical Engineering, College of Electronic and Information Engineering, Xi'an Technological University, Xi'an 710021, China.
| | - Ning Li
- Department of Biomedical Engineering, College of Electronic and Information Engineering, Xi'an Technological University, Xi'an 710021, China
| | - Fuyuan Liao
- Department of Biomedical Engineering, College of Electronic and Information Engineering, Xi'an Technological University, Xi'an 710021, China
| |
Collapse
|
|
12
|
Thomas D, Radhakrishnan P. Tumor-stromal crosstalk in pancreatic cancer and tissue fibrosis. Mol Cancer 2019; 18:14. [PMID: 30665410 PMCID: PMC6341551 DOI: 10.1186/s12943-018-0927-5] [Citation(s) in RCA: 287] [Impact Index Per Article: 47.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2018] [Accepted: 12/20/2018] [Indexed: 12/12/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with high morbidity and mortality worldwide. To date, limited therapeutic achievements targeting cell proliferation and related mechanisms has led researchers to focus on the microenvironment where pancreatic cancers develop. The anomalous proliferation of stromal cells, such as pancreatic stellate cells, and an increased deposition of altered matrix proteins create an environment that facilitates tumor growth, metastasis and drug resistance. Here, we summarize our understanding of recent advances in research about the role of fibrosis in pancreatic cancer progression, with particular emphasize on the involvement of fibrotic machineries such as wound healing, extra cellular matrix degradation, and epithelial-to-mesenchymal transition. The precise influence of these mechanisms on the biological behaviors and growth of cancer cells has great impact on clinical therapy and therefore deserves more attention. We also discuss the role of various stromal components in conferring drug resistance to PDAC which further worsening the pessimistic disease prognosis. A more in depth understanding of cancer-stroma crosstalk within the tumor microenvironment and stroma based clinical and translational therapies may provide new therapeutic strategies for the prevention of pancreatic cancer progression.
Collapse
Affiliation(s)
- Divya Thomas
- Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, 986805 Nebraska Medical Center, Omaha, NE, 68198-6805, USA
| | - Prakash Radhakrishnan
- Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, 986805 Nebraska Medical Center, Omaha, NE, 68198-6805, USA.
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA.
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA.
- Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, NE, USA.
| |
Collapse
|
|
13
|
Procacci P, Moscheni C, Sartori P, Sommariva M, Gagliano N. Tumor⁻Stroma Cross-Talk in Human Pancreatic Ductal Adenocarcinoma: A Focus on the Effect of the Extracellular Matrix on Tumor Cell Phenotype and Invasive Potential. Cells 2018; 7:cells7100158. [PMID: 30301152 PMCID: PMC6209911 DOI: 10.3390/cells7100158] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2018] [Revised: 09/27/2018] [Accepted: 10/03/2018] [Indexed: 02/07/2023] Open
Abstract
The extracellular matrix (ECM) in the tumor microenvironment modulates the cancer cell phenotype, especially in pancreatic ductal adenocarcinoma (PDAC), a tumor characterized by an intense desmoplastic reaction. Because the epithelial-to-mesenchymal transition (EMT), a process that provides cancer cells with a metastatic phenotype, plays an important role in PDAC progression, the authors aimed to explore in vitro the interactions between human PDAC cells and ECM components of the PDAC microenvironment, focusing on the expression of EMT markers and matrix metalloproteinases (MMPs) that are able to digest the basement membrane during tumor invasion. EMT markers and the invasive potential of HPAF-II, HPAC, and PL45 cells grown on different ECM substrates (fibronectin, laminin, and collagen) were analyzed. While N-cadherin, αSMA, and type I collagen were not significantly affected by ECM components, the E-cadherin/β-catenin complex was highly expressed in all the experimental conditions, and E-cadherin was upregulated by collagen in PL45 cells. Cell migration was unaffected by fibronectin and delayed by laminin. In contrast, collagen significantly stimulated cell migration and the secretion of MMPs. This study's results showed that ECM components impacted cell migration and invasive potential differently. Collagen exerted a more evident effect, providing new insights into the understanding of the intricate interplay between ECM molecules and cancer cells, in order to find novel therapeutic targets for PDAC treatment.
Collapse
Affiliation(s)
- Patrizia Procacci
- Department of Biomedical Sciences for Health, Università degli Studi di Milano, via L. Mangiagalli 31, 20133 Milan, Italy.
| | - Claudia Moscheni
- Department of Biomedical and Clinical Sciences "L. Sacco", Università degli Studi di Milano, via G.B. Grassi 74, 20157 Milan, Italy.
| | - Patrizia Sartori
- Department of Biomedical Sciences for Health, Università degli Studi di Milano, via L. Mangiagalli 31, 20133 Milan, Italy.
| | - Michele Sommariva
- Department of Biomedical Sciences for Health, Università degli Studi di Milano, via L. Mangiagalli 31, 20133 Milan, Italy.
| | - Nicoletta Gagliano
- Department of Biomedical Sciences for Health, Università degli Studi di Milano, via L. Mangiagalli 31, 20133 Milan, Italy.
| |
Collapse
|
|
14
|
Liu JF, Lee CW, Tsai MH, Tang CH, Chen PC, Lin LW, Lin CY, Lu CH, Lin YF, Yang SH, Chao CC. Thrombospondin 2 promotes tumor metastasis by inducing matrix metalloproteinase-13 production in lung cancer cells. Biochem Pharmacol 2018; 155:537-546. [PMID: 30031810 DOI: 10.1016/j.bcp.2018.07.024] [Citation(s) in RCA: 59] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2018] [Accepted: 07/18/2018] [Indexed: 01/02/2023]
Abstract
Thrombospondin (TSP)-2, a matricellular glycoprotein of the TSP family, regulates multiple biological functions, including proliferation, angiogenesis, cell adhesion, and extracellular matrix (ECM) modeling. The clinical relevance of TSP-2 has been explored in many different cancers. TSP-2 expression levels vary between different cancer types, and their role in tumor progression remains controversial. Although previous studies have reported higher serum TSP-2 levels in patients with non-small cell lung cancer, the role of TSP-2 in lung cancer progression remains to be addressed. A total of 585 lung adenocarcinoma datasets, including mRNA sequencing and clinical data, were retrieved from The Cancer Genome Atlas (TCGA). Forty paired adjacent normal tissues and lung tumor tissue datasets were used to examine TSP-2 expression levels. Tumor microarray were performed with immunohistochemical staining to examine TSP-2 expression in lung cancer patients. Transwell migration assay, quantitative real-time PCR and Western blot were used to investigate molecular mechanism of TSP-2 in lung cancer cell. TSP-2 promotes matrix metalloproteinase-13 (MMP-13) expression, cell migration, and cell invasion by mediating integrin αvβ3/FAK/Akt/NF-κB signal transduction. Using TSP-2 knockdown stable cell lines, we found that TSP-2 knockdown reduces MMP-13 expression and cell mobility. When we manipulated the tumor tissue microarray and TCGA datasets to investigate the clinical relevance of TSP-2, we found high TSP-2 expression levels in lung cancer specimens. The present study demonstrates that TSP-2 regulates cell mobility through MMP-13 expression in lung cancer cells. In addition, TSP-2 expression was associated with MMP-13 expression and poor prognosis in lung cancer. TSP-2 may therefore be a promising novel target for lung cancer treatment.
Collapse
Affiliation(s)
- Ju-Fang Liu
- Central Laboratory, Shin-Kong Wu Ho-Su Memorial Hospital, Taipei City 11101, Taiwan; Department of Medical Research, China Medical University Hospital, China Medical University, Taichung 40402, Taiwan
| | - Chiang-Wen Lee
- Division of Basic Medical Sciences, Department of Nursing, and Chronic Diseases and Health Promotion Research Center, Chang Gung University of Science and Technology, Chia-Yi 61363, Taiwan; Research Center for Industry of Human Ecology and Research Center for Chinese Herbal Medicine, Chang Gung University of Science and Technology, Taoyuan 33303, Taiwan; Department of Rehabilitation, Chang Gung Memorial Hospital, Chia-Yi 61363, Taiwan
| | - Ming-Horng Tsai
- Department of Pediatrics, Division of Neonatology and Pediatric Hematology/Oncology, Chang Gung Memorial Hospital, Yunlin 63862, Taiwan
| | - Chih-Hsin Tang
- Graduate Institute of Basic Medical Science, China Medical University, Taichung 40402, Taiwan; Department of Pharmacology, School of Medicine, China Medical University, Taichung 40402, Taiwan; Department of Biotechnology, College of Medical and Health Science, Asia University, Taichung 41354, Taiwan
| | - Po-Chun Chen
- Central Laboratory, Shin-Kong Wu Ho-Su Memorial Hospital, Taipei City 11101, Taiwan; Department of Biotechnology, College of Medical and Health Science, Asia University, Taichung 41354, Taiwan
| | - Liang-Wei Lin
- Graduate Institute of Basic Medical Science, China Medical University, Taichung 40402, Taiwan
| | - Chih-Yang Lin
- Graduate Institute of Basic Medical Science, China Medical University, Taichung 40402, Taiwan
| | - Chih-Hao Lu
- Graduate Institute of Basic Medical Science, China Medical University, Taichung 40402, Taiwan
| | - Yu-Feng Lin
- Institute of Bioinformatics and Systems Biology, National Chiao Tung University, Hsinchu 30010, Taiwan
| | - Shih-Hsing Yang
- Department of Respiratory Therapy, Fu Jen Catholic University, New Taipei City 24205, Taiwan
| | - Chia-Chia Chao
- Department of Respiratory Therapy, Fu Jen Catholic University, New Taipei City 24205, Taiwan.
| |
Collapse
|
|
15
|
Zhao C, Isenberg JS, Popel AS. Human expression patterns: qualitative and quantitative analysis of thrombospondin-1 under physiological and pathological conditions. J Cell Mol Med 2018; 22:2086-2097. [PMID: 29441713 PMCID: PMC5867078 DOI: 10.1111/jcmm.13565] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2017] [Accepted: 01/07/2018] [Indexed: 12/12/2022] Open
Abstract
Thrombospondin-1 (TSP-1), a matricellular protein and one of the first endogenous anti-angiogenic molecules identified, has long been considered a potent modulator of human diseases. While the therapeutic effect of TSP-1 to suppress cancer was investigated in both research and clinical settings, the mechanisms of how TSP-1 is regulated in cancer remain elusive, and the scientific answers to the question of whether TSP-1 expressions can be utilized as diagnostic or prognostic marker for patients with cancer are largely inconsistent. Moreover, TSP-1 plays crucial functions in angiogenesis, inflammation and tissue remodelling, which are essential biological processes in the progression of many cardiovascular diseases, and therefore, its dysregulated expressions in such conditions may have therapeutic significance. Herein, we critically analysed the literature pertaining to TSP-1 expression in circulating blood and pathological tissues in various types of cancer as well as cardiovascular and inflammation-related diseases in humans. We compare the secretion rates of TSP-1 by different cancer and non-cancer cells and discuss the potential connection between the expression changes of TSP-1 and vascular endothelial growth factor (VEGF) observed in patients with cancer. Moreover, the pattern and emerging significance of TSP-1 profiles in cardiovascular disease, such as peripheral arterial disease, diabetes and other related non-cancer disorders, are highlighted. The analysis of published TSP-1 data presented in this review may have implications for the future exploration of novel TSP-1-based treatment strategies for cancer and cardiovascular-related diseases.
Collapse
Affiliation(s)
- Chen Zhao
- Department of Biomedical EngineeringSchool of MedicineJohns Hopkins UniversityBaltimoreMDUSA
| | - Jeffrey S. Isenberg
- Division of Pulmonary, Allergy and Critical CareDepartment of MedicineHeart, Lung, Blood and Vascular Medicine InstituteUniversity of Pittsburgh School of MedicinePittsburghPAUSA
| | - Aleksander S. Popel
- Department of Biomedical EngineeringSchool of MedicineJohns Hopkins UniversityBaltimoreMDUSA
| |
Collapse
|
|
16
|
Zheng B, Peng J, Mollayup A, Bakri A, Guo L, Zheng J, Xu H. Construction of a prognostic prediction system for pancreatic ductal adenocarcinoma to investigate the key prognostic genes. Mol Med Rep 2018; 17:216-224. [PMID: 29115420 PMCID: PMC5780129 DOI: 10.3892/mmr.2017.7850] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2017] [Accepted: 09/19/2017] [Indexed: 12/16/2022] Open
Abstract
Pancreatic cancer (PC) is associated with high mortality rates and poor prognoses. Pancreatic adenocarcinoma is the most common type of PC, and almost all cases of pancreatic adenocarcinoma are pancreatic ductal adenocarcinoma (PDAC). The aim of the current study was to reveal the genes involved in the prognosis of PDAC. Five datasets, including GSE71729 (145 PDAC samples and 46 normal samples), GSE15471 (39 PDAC samples and 39 normal samples), GSE1542 (24 PDAC samples and 25 normal samples), GSE28735 (45 PDAC samples and 45 normal samples) and GSE62452 (69 PDAC samples and 69 normal samples) were downloaded from the Gene Expression Omnibus database. Using the MetaDE.ES method in the MetaDE package, differentially expressed genes (DEGs) were identified from the five datasets. Furthermore, prognosis‑associated genes were screened using the Cox regression analysis in the survival package, and co‑expression network and module analyses were performed separately using Cytoscape software and GraphWeb tool, respectively. After a prognostic prediction system was constructed and validated, enrichment analysis of the signature genes was performed using the clusterProfiler package. A total of 480 DEGs were identified from the five datasets and 259 prognosis‑associated genes were screened from GSE28735 and GSE62452. In addition, the prognostic prediction system composed of 67 signature genes [including basic transcription factor 3 (BTF3), serine/threonine kinase 11 (STK11), thrombospondin 1 (THBS1), ribosomal protein L38 (RPL38) and secretin receptor (SCTR)] was constructed and validated. The signature genes involved in the co‑expression network were enriched in five pathways. In particular, STK11 was involved in three signaling pathways, and THBS1 was enriched in the phosphoinositide 3‑kinase‑Akt signaling pathway. Thus, BTF3, STK11, THBS1, RPL38 and SCTR may influence the prognosis of PDAC.
Collapse
Affiliation(s)
- Bingli Zheng
- Department of Pancreatic Surgery, Xinjiang Uygur Autonomous Region People's Hospital, Ürümqi, Xinjiang 830002, P.R. China
| | - Jie Peng
- Emergency Department, Traditional Chinese Medicine Hospital of Xinjiang Medical University, Ürümqi, Xinjiang 830000, P.R. China
| | - Ablikim Mollayup
- Department of Pancreatic Surgery, Xinjiang Uygur Autonomous Region People's Hospital, Ürümqi, Xinjiang 830002, P.R. China
| | - Ahmat Bakri
- Department of Pancreatic Surgery, Xinjiang Uygur Autonomous Region People's Hospital, Ürümqi, Xinjiang 830002, P.R. China
| | - Lei Guo
- Department of Pancreatic Surgery, Xinjiang Uygur Autonomous Region People's Hospital, Ürümqi, Xinjiang 830002, P.R. China
| | - Jianjiang Zheng
- Department of Pancreatic Surgery, Xinjiang Uygur Autonomous Region People's Hospital, Ürümqi, Xinjiang 830002, P.R. China
| | - Hui Xu
- Department of Pancreatic Surgery, Xinjiang Uygur Autonomous Region People's Hospital, Ürümqi, Xinjiang 830002, P.R. China
| |
Collapse
|
|
17
|
Feygenzon V, Loewenstein S, Lubezky N, Pasmanic-Chor M, Sher O, Klausner JM, Lahat G. Unique cellular interactions between pancreatic cancer cells and the omentum. PLoS One 2017. [PMID: 28632775 PMCID: PMC5478139 DOI: 10.1371/journal.pone.0179862] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
Pancreatic cancer is a common cause of cancer-related mortality. Omental spread is frequent and usually represents an ominous event, leading to patient death. Omental metastasis has been studied in ovarian cancer, but data on its role in pancreatic cancer are relatively scarce and the molecular biology of this process has yet to be explored. We prepared tissue explants from human omental fat, and used conditioned medium from the explants for various in vitro and in vivo experiments designed to evaluate pancreatic cancer development, growth, and survival. Mass spectrometry identified the fat secretome, and mRNA array identified specific fat-induced molecular alternations in tumor cells. Omental fat increased pancreatic cancer cellular growth, migration, invasion, and chemoresistance. We identified diverse potential molecules secreted by the omentum, which are associated with various pro-tumorigenic biological processes. Our mRNA array identified specific omental-induced molecular alternations that are associated with cancer progression and metastasis. Omental fat increased the expression of transcription factors, mRNA of extracellular matrix proteins, and adhesion molecules. In support with our in vitro data, in vivo experiments demonstrated an increased pancreatic cancer tumor growth rate of PANC-1 cells co-cultured for 24 hours with human omental fat conditioned medium. Our results provide novel data on the role of omental tissue in omental metastases of pancreatic cancer. They imply that omental fat secreted factors induce cellular reprogramming of pancreatic cancer cells, resulting in increased tumor aggressiveness. Understanding the mechanisms of omental metastases may enable us to discover new potential targets for therapy.
Collapse
Affiliation(s)
- Valerya Feygenzon
- Sackler School of Medicine, The Nicholas and Elizabeth Cathedra of Experimental Surgery, Tel Aviv University, Tel Aviv, Israel
| | - Shelly Loewenstein
- Department of Surgery, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
- * E-mail:
| | - Nir Lubezky
- Sackler School of Medicine, The Nicholas and Elizabeth Cathedra of Experimental Surgery, Tel Aviv University, Tel Aviv, Israel
- Department of Surgery, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
| | | | - Osnat Sher
- Sackler School of Medicine, The Nicholas and Elizabeth Cathedra of Experimental Surgery, Tel Aviv University, Tel Aviv, Israel
- Department of Pathology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
| | - Joseph M. Klausner
- Sackler School of Medicine, The Nicholas and Elizabeth Cathedra of Experimental Surgery, Tel Aviv University, Tel Aviv, Israel
- Department of Surgery, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
| | - Guy Lahat
- Sackler School of Medicine, The Nicholas and Elizabeth Cathedra of Experimental Surgery, Tel Aviv University, Tel Aviv, Israel
- Department of Surgery, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
| |
Collapse
|
|
18
|
Narayanan S, Loganathan G, Dhanasekaran M, Tucker W, Patel A, Subhashree V, Mokshagundam S, Hughes MG, Williams SK, Balamurugan AN. Intra-islet endothelial cell and β-cell crosstalk: Implication for islet cell transplantation. World J Transplant 2017; 7:117-128. [PMID: 28507914 PMCID: PMC5409911 DOI: 10.5500/wjt.v7.i2.117] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2017] [Revised: 02/28/2017] [Accepted: 03/24/2017] [Indexed: 02/05/2023] Open
Abstract
The intra-islet microvasculature is a critical interface between the blood and islet endocrine cells governing a number of cellular and pathophysiological processes associated with the pancreatic tissue. A growing body of evidence indicates a strong functional and physical interdependency of β-cells with endothelial cells (ECs), the building blocks of islet microvasculature. Intra-islet ECs, actively regulate vascular permeability and appear to play a role in fine-tuning blood glucose sensing and regulation. These cells also tend to behave as “guardians”, controlling the expression and movement of a number of important immune mediators, thereby strongly contributing to the physiology of islets. This review will focus on the molecular signalling and crosstalk between the intra-islet ECs and β-cells and how their relationship can be a potential target for intervention strategies in islet pathology and islet transplantation.
Collapse
|
|
19
|
Yin JH, Zhu XY, Shi WD, Liu LM. Huachansu injection inhibits metastasis of pancreatic cancer in mice model of human tumor xenograft. Altern Ther Health Med 2014; 14:483. [PMID: 25496480 PMCID: PMC4320457 DOI: 10.1186/1472-6882-14-483] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2013] [Accepted: 09/30/2014] [Indexed: 12/17/2022]
Abstract
Background Huachansu injection (HCS) is a water-soluble preparation made from Bufo gargarizans’s skin, which has been widely used in clinics for tumor therapy in China. Though the anti-cancer activity of HCS has been verified through studies in vitro and in vivo, there is little research about its potential anti-metastasis effect. The primary objective of this study was to assess the effects of HCS on both the invasion of pancreatic cancer cells in vitro and on the progression of liver metastasis in vivo in this study. Methods HCS anti-metastasis potential was accessed using both assay of Cell viability and invasion in vitro, and then further Establishing xenograft model in nude mice. In the cell-based assay, mRNA and protein expression of MMP-2, MMP-9 and VEGF was detected by semi-quantitative RT-PCR and western blotting. In animal experiment, liver metastasis nodules and change of liver-body ratio was observed. Meanwhile, correlation of the CA19-9 and CEA content in serum with the progression of liver metastasis was analyzed. Result We observed that HCS prevented the invasion of cancer cells, with inhibiting the expressions of MMP-2 and MMP-9, and reduced not only the number of metastasis nodules but the ratio of liver-body weight as well. Furthermore, HCS decreased the expression of MMP-2, MMP-9 and VEGF in liver metastasis, while also reducing CA19-9 contents in serum. In addition, correlation analysis indicated that the level of CA19-9 in serum was closely related to the number of liver metastasis nodules. Conclusion Our experimental results suggest that HCS has some anti-metastasis potential to suppress the growth of liver metastasis by decreasing the expression of MMP-2 and MMP-9 as well as VEGF. Electronic supplementary material The online version of this article (doi:10.1186/1472-6882-14-483) contains supplementary material, which is available to authorized users.
Collapse
|
|
20
|
Lunardi S, Muschel RJ, Brunner TB. The stromal compartments in pancreatic cancer: are there any therapeutic targets? Cancer Lett 2013; 343:147-55. [PMID: 24141189 DOI: 10.1016/j.canlet.2013.09.039] [Citation(s) in RCA: 126] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2013] [Revised: 09/25/2013] [Accepted: 09/26/2013] [Indexed: 12/16/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is characterised by an abundant stromal response also known as a desmoplastic reaction. Pancreatic Stellate Cells have been identified as playing a key role in pancreatic cancer desmoplasia. There is accumulating evidence that the stroma contributes to tumour progression and to the low therapeutic response of PDAC patients. In this review we described the main actors of the desmoplastic reaction within PDAC and novel therapeutic approaches that are being tested to block the detrimental function of the stroma.
Collapse
Affiliation(s)
- Serena Lunardi
- Gray Institute for Radiation Oncology and Biology, Department of Oncology, University of Oxford, Churchill Hospital, RRI, Oxford OX3 7LJ, UK
| | - Ruth J Muschel
- Gray Institute for Radiation Oncology and Biology, Department of Oncology, University of Oxford, Churchill Hospital, RRI, Oxford OX3 7LJ, UK
| | - Thomas B Brunner
- Gray Institute for Radiation Oncology and Biology, Department of Oncology, University of Oxford, Churchill Hospital, RRI, Oxford OX3 7LJ, UK; Department of Radiation Oncology, University Hospitals Freiburg, Robert-Koch-Straße 3, 79106 Freiburg, Germany.
| |
Collapse
|
|
21
|
Radziwon-Balicka A, Santos-Martinez MJ, Corbalan JJ, O'Sullivan S, Treumann A, Gilmer JF, Radomski MW, Medina C. Mechanisms of platelet-stimulated colon cancer invasion: role of clusterin and thrombospondin 1 in regulation of the P38MAPK-MMP-9 pathway. Carcinogenesis 2013; 35:324-32. [DOI: 10.1093/carcin/bgt332] [Citation(s) in RCA: 65] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
|
|
22
|
Miyata Y, Watanabe SI, Kanetake H, Sakai H. Thrombospondin-1-derived 4N1K peptide expression is negatively associated with malignant aggressiveness and prognosis in urothelial carcinoma of the upper urinary tract. BMC Cancer 2012; 12:372. [PMID: 22928942 PMCID: PMC3502595 DOI: 10.1186/1471-2407-12-372] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2012] [Accepted: 08/09/2012] [Indexed: 12/18/2022] Open
Abstract
Background Thrombospondin (TSP) is a multi-functional protein that appears to have dual roles in cancer, that is, either as a promoter or a suppressor. 4N1K is a TSP-derived peptide that has been reported to be associated with neovascularity, cell survival, and invasion. There is a little information regarding its pathological roles in human cancer tissues. Our aim was to clarify clinical significance and prognostic value of 4N1K expression in patients with urothelial carcinoma of the upper urinary tract (UC-UUT). Methods We investigated 4N1K expression in 97 surgically excised, non-metastasized UC-UUT specimens and five normal tissues via immunohistochemistry. Microvessel density (MVD), lymph vessel density (LVD), cancer cell proliferation (PI), apoptotic index (AI), and matrix metalloproteinase (MMP)-9 expression was also determined. The relationships 4N1K expression and pT stage, grade, and prognosis were analysed. In addition, correlations with these cancer-related and TSP-related factors were also investigated. Results Strong and moderate 4N1K expression was found in normal urothelial tissues. Of the 97 specimens, 45 patients were positive for 4N1K expression, which was primarily located in the interstitial areas of the cancer tissue. 4N1K expression was negatively associated with pT stage (p = 0.003) and grade (p = 0.002). Survival analyses revealed that 4N1K is a predictor of metastasis-free (p = 0.036) and cause-specific survival (p = 0.009). 4N1K expression was closely associated with malignant behaviour, specifically MVD (p = 0.001), AI (p = 0.013), and MMP-9 expression (p = 0.036), but not PI and LVD, as determined via multivariate analysis models. Conclusions 4N1K expression appears to be associated with cancer cell progression and survival in UC-UUT patients via the regulation of angiogenesis, apoptosis, and MMP-9 expression. There is a possibility that the 4N1K-peptide may be a useful marker and novel therapeutic target in patients with UC-UUT.
Collapse
Affiliation(s)
- Yasuyoshi Miyata
- Department of Nephro-Urology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
| | | | | | | |
Collapse
|
|
23
|
Wang XH, Cheng YS. Advances in magnetic resonance molecular and functional imaging to diagnose pancreatic cancer. Shijie Huaren Xiaohua Zazhi 2012; 20:2063-2069. [DOI: 10.11569/wcjd.v20.i22.2063] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Pancreatic cancer has a high mortality rate, which is generally related to the initial diagnosis coming at late stage disease combined with a lack of effective diagnostic techniques. Over the past few years, molecular-functional imaging, which can be defined as the in vivo characterization and measurement of biologic processes at the molecular and gene levels, has developed rapidly and allows diagnosing pancreatic cancer more early and specifically. Magnetic resonance (MR) imaging is widely used for molecular imaging because of the high spatial resolution. This paper reviews recent advances in MR molecular and functional imaging to diagnose pancreatic cancer.
Collapse
|
|
24
|
Henkin J, Volpert OV. Therapies using anti-angiogenic peptide mimetics of thrombospondin-1. Expert Opin Ther Targets 2011; 15:1369-86. [PMID: 22136063 DOI: 10.1517/14728222.2011.640319] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
INTRODUCTION The role of hrombospondin-1 (TSP1) as a major endogenous angiogenesis inhibitor has been confirmed by numerous studies and subsequent mechanistic discoveries. It has yielded a new class of potential drugs against cancer and other angiogenesis-driven diseases. AREAS COVERED An overview of TSP1 functions and molecular mechanisms, including regulation and signaling. Functions in endothelial and non-endothelial cells, with emphasis on the role of TSP1 in the regulation of angiogenesis and inflammation. The utility of duplicating these activities for drug discovery. Past and current literature on endogenous TSP1 and its role in the progression of cancer and non-cancerous pathological conditions is summarized, as well as the research undertaken to identify and optimize short bioactive peptides derived from the two TSP1 anti-angiogenic domains, which bind CD47 and CD36 cell surface receptors. Lastly, there is an overview of the efficacy of some of these peptides in pre-clinical and clinical models of angiogenesis-dependent disease. EXPERT OPINION It is concluded that TSP1-derived peptides and peptide mimetics hold great promise as future agents for the treatment of cancer and other diseases driven by excessive angiogenesis. They may fulfill unmet medical needs including neovascular ocular disease and the diseases of the female reproductive tract including ovarian cancer.
Collapse
Affiliation(s)
- Jack Henkin
- Chemistry of Life Processes Institute, Northwestern University, 2145 Sheridan Road, Evanston, IL 60208, USA
| | | |
Collapse
|
|
25
|
Thrombospondin-1 (TSP-1) Stimulates Expression of Integrin alpha6 in Human Breast Carcinoma Cells: A Downstream Modulator of TSP-1-Induced Cellular Adhesion. JOURNAL OF ONCOLOGY 2010; 2010:645376. [PMID: 20631908 PMCID: PMC2902750 DOI: 10.1155/2010/645376] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/27/2009] [Revised: 03/17/2010] [Accepted: 05/20/2010] [Indexed: 11/20/2022]
Abstract
Thrombospondin-1 (TSP-1) is involved in a variety of different cellular processes including cell adhesion, tumor progression, and angiogenesis. This paper reports the novel finding that TSP-1 upregulates integrin α6 subunit in human keratinocytes and human breast cancer cells resulting in increased cell adhesion and tumor cell invasion. The effect of TSP-1 on α6 subunit expression was examined in human keratinocytes and breast adenocarcinoma cell lines (MDA-MB-231) treated with TSP-1 and in TSP-1 stably transfected breast cancer cells. TSP-1 upregulated α6 message and protein in these cells as revealed by differential display, Northern and Western blot analysis and immunohistochemical localization studies. The increased expression of α6 was shown to mediate adhesion and invasion of these cells to laminin, a major component of the basement membrane and extracellular matrix (ECM). These data suggest that TSP-1 plays an integral role in the attachment of cells to the ECM facilitating cell motility and angiogenesis.
Collapse
|
|
26
|
Extracellular matrix proteins and tumor angiogenesis. JOURNAL OF ONCOLOGY 2010; 2010:586905. [PMID: 20671917 PMCID: PMC2910498 DOI: 10.1155/2010/586905] [Citation(s) in RCA: 56] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/02/2009] [Accepted: 05/26/2010] [Indexed: 01/09/2023]
Abstract
Tumor development is a complex process that relies on interaction and communication
between a number of cellular compartments. Much of the mass of a solid tumor is comprised of
the stroma which is richly invested with extracellular matrix. Within this matrix are a host of
matricellular proteins that regulate the expression and function of a myriad of proteins that
regulate tumorigenic processes. One of the processes that is vital to tumor growth and
progression is angiogenesis, or the formation of new blood vessels from preexisting vasculature.
Within the extracellular matrix are structural proteins, a host of proteases, and resident pro- and
antiangiogenic factors that control tumor angiogenesis in a tightly regulated fashion. This paper discusses the role that the extracellular matrix and ECM proteins play in the regulation of tumor angiogenesis.
Collapse
|
|
27
|
Abstract
Pancreatic cancer represents a major challenge for research studies and clinical management. No specific tumor marker for the diagnosis of pancreatic cancer exists. Therefore, extensive genomic, transcriptomic, and proteomic studies are being developed to identify candidate markers for use in high-throughput systems capable of large cohort screening. Understandably, the complex pathophysiology of pancreatic cancer requires sensitive and specific biomarkers that can improve both early diagnosis and therapeutic monitoring. The lack of a single diagnostic marker makes it likely that only a panel of biomarkers is capable of providing the appropriate combination of high sensitivity and specificity. Biomarker discovery using novel technology can improve prognostic upgrading and pinpoint new molecular targets for innovative therapy.
Collapse
|
|
28
|
Liebig C, Wilks JA, Feig BW, Wang TN, Wilson M, Herdman AV, Albo D. The role of angiocidin in sarcomas. Cancer 2009; 115:5251-62. [DOI: 10.1002/cncr.24568] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
|
|
29
|
Velasco P, Huegel R, Brasch J, Schröder JM, Weichenthal M, Stockfleth E, Schwarz T, Lawler J, Detmar M, Lange-Asschenfeldt B. The angiogenesis inhibitor thrombospondin-1 inhibits acute cutaneous hypersensitivity reactions. J Invest Dermatol 2009; 129:2022-30. [PMID: 19194474 DOI: 10.1038/jid.2008.447] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
There is increasing evidence that vascular remodeling and endothelial cell activation promote acute and chronic inflammation. Thrombospondin 1 (TSP-1) is a potent endogenous angiogenesis inhibitor thought to play an important role in maintaining cutaneous vascular quiescence. We first investigated TSP-1 expression in human and contact hypersensitivity (CHS) reactions and found that TSP-1 was upregulated in the inflamed skin of patients and in mice. To elucidate the function of TSP-1 in cutaneous inflammation, we induced CHS reactions in the skin of mice with targeted epidermal TSP-1 overexpression in TSP-1-deficient mice and in wild-type mice. We found decreased edema formation, angiogenesis, and inflammatory infiltrate in the inflamed skin of TSP-1 transgenic mice. Conversely, TSP-1-deficient mice exhibited an enhanced and prolonged inflammation, characterized by increased edema formation, enhanced vascular remodeling, and increased neutrophilic infiltrate, when compared with wild-type mice. Moreover, we found strong upregulation of the proinflammatory cytokines IL-1beta, macrophage inflammatory protein 2, and tumor necrosis factor-alpha in the inflamed skin of TSP-1-deficient mice. Our results indicate that TSP-1 downregulates cutaneous delayed-type hypersensitivity reactions by acting on several distinct pathways mediating skin inflammation.
Collapse
Affiliation(s)
- Paula Velasco
- Department of Dermatology, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
30
|
Farrow B, Albo D, Berger DH. The Role of the Tumor Microenvironment in the Progression of Pancreatic Cancer. J Surg Res 2008; 149:319-28. [DOI: 10.1016/j.jss.2007.12.757] [Citation(s) in RCA: 110] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2007] [Revised: 08/01/2007] [Accepted: 12/06/2007] [Indexed: 12/12/2022]
|
|
31
|
Nakchbandi IA, Löhr JM. Coagulation, anticoagulation and pancreatic carcinoma. NATURE CLINICAL PRACTICE. GASTROENTEROLOGY & HEPATOLOGY 2008; 5:445-455. [PMID: 18594494 DOI: 10.1038/ncpgasthep1184] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/10/2008] [Accepted: 05/15/2008] [Indexed: 12/11/2022]
Abstract
An increase in coagulation in patients with pancreatic carcinoma has long been documented. In this Review, we present what is known about the pathophysiology of increased coagulation in cancer and how it applies to pancreatic carcinoma. The relationship between the activation of coagulation or symptomatic thromboembolic disease and the development of pancreatic carcinoma is explored. Data on the relationship between thromboembolic disease and the behavior of pancreatic cancer before, during or after a diagnosis is made are also reviewed. Finally, the rationale and evidence for the use of oral anticoagulants or heparin in patients with pancreatic carcinoma is presented. This Review is a critical appraisal of what is known, and when the evidence is acceptable, on the subject of thromboembolism, anticoagulation, and treatment with anticoagulants in patients with pancreatic carcinoma.
Collapse
Affiliation(s)
- Inaam A Nakchbandi
- Max-Planck Institute for Biochemistry, Martinsried, Germany and the University of Heidelberg, Heidelberg, Germany
| | | |
Collapse
|
|
32
|
Abstract
BACKGROUND Pancreatic cancer remains one of the most lethal of all solid tumours of the gastrointestinal tract. It is characterized by late diagnosis, aggressive local invasion, early metastasis and resistance to chemoradiotherapy. Increasing knowledge regarding the molecular events behind the growth and invasion of pancreatic cancer may lead to new targets for intervention. METHODS A search of Pubmed and Medline databases was undertaken using the keywords pancreatic cancer, gastrointestinal cancer, hypoxia, angiogenesis and anti-angiogenesis therapy. RESULTS Hypoxia is the driving force behind angiogenesis in pancreatic cancers. Research into angiogenesis has shown many different sites that can be targeted by agents such as tyrosine kinase inhibitors. CONCLUSION Anti-angiogenic therapy could be an important adjunct to conventional chemotherapy treatment of gastrointestinal neoplasia.
Collapse
Affiliation(s)
- Giuseppe Garcea
- Department of Hepatobiliary Surgery, The Leicester General Hospital, Leicester, UK.
| | | | | | | | | |
Collapse
|
|
33
|
Kilian M, Gregor JI, Heukamp I, Hanel M, Ahlgrimm M, Schimke I, Kristiansen G, Ommer A, Walz MK, Jacobi CA, Wenger FA. Matrix metalloproteinase inhibitor RO 28-2653 decreases liver metastasis by reduction of MMP-2 and MMP-9 concentration in BOP-induced ductal pancreatic cancer in Syrian Hamsters: inhibition of matrix metalloproteinases in pancreatic cancer. Prostaglandins Leukot Essent Fatty Acids 2006; 75:429-34. [PMID: 17034997 DOI: 10.1016/j.plefa.2006.08.004] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2006] [Accepted: 08/25/2006] [Indexed: 01/17/2023]
Abstract
BACKGROUND Matrix metalloproteinases (MMP) are proteolytic enzymes which degrade the extracellular matrix and therefore play an important role in metastasis. However, the impact of MMP inhibitors (MMPI) on pancreatic cancer is still unclear. Thus we evaluated the influence of selective MMPI Ro 28-2653 on the incidence of liver metastases and the concentration of MMP-2 and MMP-9 in ductal pancreatic adenocarcinoma in Syrian hamster. MATERIAL AND METHODS One hundred and thirty male Syrian hamsters were randomised into 8 groups (Gr.1-3: n=15, Gr.4-8: n=17). Pancreatic cancer was induced by weekly subcutaneous injection of 10mg N-nitrosobis-2-oxopropylamin (BOP)/kg body weight (Gr.4-8) while healthy control Gr. 1-3 received 0.5 ml sodium chloride 0.9%. Gr.1 and 4 had free access to a standard diet, Gr. 2, 3 and 5-8 received a diet rich in polyunsaturated fatty acids, which increases liver metastasis in this model. In week 17 oral therapy started: Gr.3 and 6: 60 mg Eudragit/kg body weight/d (vehicle of MMPI), Gr.7 and 8: 40 mg, respectively, 120 mg RO 28-2653/kg body weight/d; Gr.1, 2, 4, 5: no therapy. After 30 weeks all hamsters were sacrificed and histopathologically examined. Additionally concentrations of MMP-2 and MMP-9 were measured in non-metastatic liver and liver metastases. RESULTS Concentrations of MMP-2 and MMP-9 in liver metastases were decreased by high- and low-dose therapy with MMPI. Furthermore, the incidence of liver metastases was significantly reduced by low-dose therapy with Ro 28-2653. CONCLUSION Low-dose therapy with Ro 28-2653 decreased liver metastasis due to an inhibition of MMP-2 and MMP-9 concentration in ductal pancreatic cancer.
Collapse
Affiliation(s)
- M Kilian
- Clinic of General, Visceral, Vascular and Thoracic Surgery, Charité Campus Mitte, Universitätsmedizin in Berlin, Schumannstr. 20/21, 10117 Berlin, Germany.
| | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
34
|
Cummins PM, von Offenberg Sweeney N, Killeen MT, Birney YA, Redmond EM, Cahill PA. Cyclic strain-mediated matrix metalloproteinase regulation within the vascular endothelium: a force to be reckoned with. Am J Physiol Heart Circ Physiol 2006; 292:H28-42. [PMID: 16951049 DOI: 10.1152/ajpheart.00304.2006] [Citation(s) in RCA: 60] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
The vascular endothelium is a dynamic cellular interface between the vessel wall and the bloodstream, where it regulates the physiological effects of humoral and biomechanical stimuli on vessel tone and remodeling. With respect to the latter hemodynamic stimulus, the endothelium is chronically exposed to mechanical forces in the form of cyclic circumferential strain, resulting from the pulsatile nature of blood flow, and shear stress. Both forces can profoundly modulate endothelial cell (EC) metabolism and function and, under normal physiological conditions, impart an atheroprotective effect that disfavors pathological remodeling of the vessel wall. Moreover, disruption of normal hemodynamic loading can be either causative of or contributory to vascular diseases such as atherosclerosis. EC-matrix interactions are a critical determinant of how the vascular endothelium responds to these forces and unquestionably utilizes matrix metalloproteinases (MMPs), enzymes capable of degrading basement membrane and interstitial matrix molecules, to facilitate force-mediated changes in vascular cell fate. In view of the growing importance of blood flow patterns and mechanotransduction to vascular health and pathophysiology, and considering the potential value of MMPs as therapeutic targets, a timely review of our collective understanding of MMP mechanoregulation and its impact on the vascular endothelium is warranted. More specifically, this review primarily summarizes our current knowledge of how cyclic strain regulates MMP expression and activation within the vascular endothelium and subsequently endeavors to address the direct and indirect consequences of this on vascular EC fate. Possible relevance of these phenomena to vascular endothelial dysfunction and pathological remodeling are also addressed.
Collapse
Affiliation(s)
- Philip M Cummins
- Vascular Health Research Centre, Faculty of Science and Health, Dublin City Univ., Dublin, Ireland.
| | | | | | | | | | | |
Collapse
|
|
35
|
Zhang X, Galardi E, Duquette M, Lawler J, Parangi S. Antiangiogenic treatment with three thrombospondin-1 type 1 repeats versus gemcitabine in an orthotopic human pancreatic cancer model. Clin Cancer Res 2006; 11:5622-30. [PMID: 16061881 DOI: 10.1158/1078-0432.ccr-05-0459] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
PURPOSE In this study, we investigated the antitumor efficacy of thrombospondin-1 three type 1 repeats (3TSR), the antiangiogenic domain of thrombospondin-1, in comparison and in combination with gemcitabine, in an orthotopic pancreatic cancer model. EXPERIMENTAL DESIGN Human pancreatic cancer cells were injected into the pancreas of severe combined immunodeficient mice. The animals were treated with 3TSR, gemcitabine, 3TSR plus gemcitabine, or vehicle for 3 weeks. Subsequently, the effects of 3TSR and/or gemcitabine on tumor growth, tumor necrosis, microvessel density, cancer cell proliferation, apoptosis, and endothelial cell apoptosis were analyzed. RESULTS After 3 weeks of treatment, 3TSR reduced tumor volume by 65%, and gemcitabine by 84%. Tumor volume was not statistically different between gemcitabine group and combinatorial treatment group. Extensive necrotic areas were observed in tumors from 3TSR-treated mice, whereas tumors from gemcitabine and combinatorially treated mice were less necrotic than control tumors. 3TSR reduced tumor microvessel density and increased tumor blood vessel endothelial cell apoptosis. In contrast, gemcitabine induced apoptosis and inhibited proliferation of cancer cells. CONCLUSION 3TSR, the antiangiogenic domain of thrombospondin-1, showed comparable antitumor efficacy to gemcitabine in a human pancreatic cancer orthotopic mouse model. No synergistic effect was found when the two drugs were combined and possible reasons are discussed in detail. A delicate balance between normalization and excessive regression of tumor vasculature is important when initiating alternative combinatorial regimens for treatment of patients with pancreatic cancer.
Collapse
Affiliation(s)
- Xuefeng Zhang
- Department of Surgery and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA
| | | | | | | | | |
Collapse
|
|
36
|
Hiscott P, Paraoan L, Choudhary A, Ordonez JL, Al-Khaier A, Armstrong DJ. Thrombospondin 1, thrombospondin 2 and the eye. Prog Retin Eye Res 2006; 25:1-18. [PMID: 15996506 DOI: 10.1016/j.preteyeres.2005.05.001] [Citation(s) in RCA: 58] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Thrombospondin 1 and thrombospondin 2 (TSP1 and TSP2), which comprise the subgroup A thrombospondins, are matricellular proteins. As matricellular proteins, they modulate interactions between cells and the cellular environment, regulate cell adhesion and typically are expressed during tissue formative processes. In general, TSP1 and TSP2 counter angiogenesis (including tumour angiogenesis) and play important but contrasting roles during cutaneous repair. The two proteins are involved in development, including that of the eye, although evidence suggests that they have their greatest impact during tissue production in the adult. In the normal adult eye, they tend to be found at sites of ongoing matrix synthesis or cell-matrix interactions. At these sites, the two proteins possibly influence cellular differentiation and/or basement membrane deposition. TSP1 is also present in the intraocular fluids and drainage pathway, where it may function in maintaining the anti-angiogenic environment and in intraocular pressure control, respectively. TSP1 could also be involved in ocular immune privilege. Unlike in skin wounds, where TSP1 is derived from the blood and is present only in the early phases of repair, ocular tissue damage appears to lead to protacted TSP1 synthesis by local cells. This response might help suppress angiogenesis in the transparent tissues of the eye and so lessen visual axis opacification following injury. However, TSP2, which is also produced by damaged ophthalmic tissue and may be especially important in matrix organisation, seems to augment contraction in anomalous intraocular fibrosis. Elucidating the roles of TSP1 and TSP2 in ocular physiology and pathobiology may lead to improved therapies for neovascular, neoplastic, reparative and other ophthalmic diseases.
Collapse
Affiliation(s)
- Paul Hiscott
- Unit of Ophthalmology, School of Clinical Science, University Clinical Departments, The Duncan Building, University of Liverpool, Daulby Street, Liverpool L69 3GA, UK.
| | | | | | | | | | | |
Collapse
|
|
37
|
Ren B, Yee KO, Lawler J, Khosravi-Far R. Regulation of tumor angiogenesis by thrombospondin-1. Biochim Biophys Acta Rev Cancer 2005; 1765:178-88. [PMID: 16406676 DOI: 10.1016/j.bbcan.2005.11.002] [Citation(s) in RCA: 102] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2005] [Revised: 11/27/2005] [Accepted: 11/28/2005] [Indexed: 01/11/2023]
Abstract
Angiogenesis plays a critical role in the growth and metastasis of tumors. Thrombospondin-1 (TSP-1) is a potent angiogenesis inhibitor, and down-regulation of TSP-1 has been suggested to alter tumor growth by modulating angiogenesis in a variety of tumor types. Expression of TSP-1 is up-regulated by the tumor suppressor gene, p53, and down-regulated by oncogenes such as Myc and Ras. TSP-1 inhibits angiogenesis by inhibiting endothelial cell migration and proliferation and by inducing apoptosis. In addition, activation of transforming growth factor beta (TGF-beta) by TSP-1 plays a crucial role in the regulation of tumor progression. An understanding of the molecular basis of TSP-1-mediated inhibition of angiogenesis and tumor progression will aid in the development of novel therapeutics for the treatment of cancer.
Collapse
Affiliation(s)
- Bin Ren
- Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
| | | | | | | |
Collapse
|
|
38
|
Garcea G, Neal CP, Pattenden CJ, Steward WP, Berry DP. Molecular prognostic markers in pancreatic cancer: a systematic review. Eur J Cancer 2005; 41:2213-36. [PMID: 16146690 DOI: 10.1016/j.ejca.2005.04.044] [Citation(s) in RCA: 183] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2005] [Accepted: 04/08/2005] [Indexed: 12/30/2022]
Abstract
Pancreatic cancer is one of the most lethal tumours of the gastrointestinal tract. The ability to predict which patients would benefit most from surgical intervention and/or chemotherapy would be a great clinical asset. Considerable research has focused on identifying molecular events in pancreatic carcinogenesis, and their correlation with clinicopathological variables of pancreatic tumours and survival. This systematic review examined evidence from published manuscripts looking at molecular markers in pancreatic cancer and their correlation with tumour stage and grade, response to chemotherapy and long-term survival. A literature search was undertaken using PubMed and MEDLINE search engines, using the keywords p53, p21, p16, p27, SMAD4, K-ras, cyclin D1, Bax, Bcl-2, EGFR, EGF, c-erbB2, HB-EGF, TGFbeta, FGF, MMP, uPA, cathepsin, heparanase, E-cadherin, laminins, integrins, TMSF, CD44, cytokines, angiogenesis, VEGF, IL-8, beta-catenin, DNA microarray, and gene profiling. A bewildering number of biomarkers are currently under evaluation. For the most part, the evidence regarding their application as prognostic indicators is conflicting. The advent of gene microarray and mass spectrometric protein profiling offers the potential to examine many different biomarkers simultaneously. This 'protein/gene signature' could revolutionise work in this field and allow researchers to develop accurate and reproducible predictions of survival based on protein or gene profiles.
Collapse
Affiliation(s)
- G Garcea
- Cancer Studies and Molecular Medicine, The Robert Kilpatrick Clinical Sciences Building, University of Leicester, The Leicester Royal Infirmary, Leicester LE2 7LX, UK.
| | | | | | | | | |
Collapse
|
|
39
|
Zhang X, Galardi E, Duquette M, Delic M, Lawler J, Parangi S. Antiangiogenic treatment with the three thrombospondin-1 type 1 repeats recombinant protein in an orthotopic human pancreatic cancer model. Clin Cancer Res 2005; 11:2337-44. [PMID: 15788685 DOI: 10.1158/1078-0432.ccr-04-1900] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
PURPOSE This study investigates the antiangiogenesis and antitumor efficacy of a recombinant protein composed of the three type 1 repeats (3TSR) of thrombospondin-1 in an orthotopic human pancreatic cancer model and provides useful preclinical data for pancreatic cancer treatment. EXPERIMENTAL DESIGN Human pancreatic cancer cells (AsPC-1) were injected into the pancreas of severe combined immunodeficient mice. The animals were treated with 3TSR (3 mg per kg per day) or PBS for 3 weeks. Subsequently, the effects of 3TSR on tumor growth, microvessel density, cancer cell proliferation, apoptosis, and endothelial cell apoptosis were analyzed. The in vitro effects of 3TSR on human pancreatic cancer cells were also studied. RESULTS 3TSR treatment significantly reduced angiogenesis and tumor growth of orthotopic pancreatic cancer. 3TSR-treated mice had a 69% reduction in tumor volume (316.6 +/- 79.3 versus 1,012.2 +/- 364.5 mm(3); P = 0.0001), and a significant increase in tumor necrotic area. After 3TSR treatment, both the vessel number and average microvessel size were significantly decreased, and microvessel density was decreased from 8.0% to 3.7% (P < 0.0001). The apoptotic rate of tumoral endothelial cells in 3TSR-treated tumors increased to 14.7% comparing to 4.2% in control tumors (P < 0.0001). 3TSR showed no direct effects on pancreatic cancer cell proliferation or apoptosis either in vivo or in vitro. CONCLUSION 3TSR, a domain of a natural occurring angiogenesis inhibitor, showed potent therapeutic effect in pancreatic cancer by inhibiting tumor angiogenesis and may prove to be a promising agent for clinical pancreatic cancer treatment.
Collapse
Affiliation(s)
- Xuefeng Zhang
- Departments of Surgery and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, MA 02215, USA
| | | | | | | | | | | |
Collapse
|
|
40
|
Von Offenberg Sweeney N, Cummins PM, Cotter EJ, Fitzpatrick PA, Birney YA, Redmond EM, Cahill PA. Cyclic strain-mediated regulation of vascular endothelial cell migration and tube formation. Biochem Biophys Res Commun 2005; 329:573-82. [PMID: 15737624 DOI: 10.1016/j.bbrc.2005.02.013] [Citation(s) in RCA: 73] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2005] [Indexed: 11/20/2022]
Abstract
UNLABELLED Hemodynamic forces exerted by blood flow (cyclic strain, shear stress) affect the initiation and progression of angiogenesis; however, the precise signaling mechanism(s) involved are unknown. In this study, we examine the role of cyclic strain in regulating bovine aortic endothelial cell (BAEC) migration and tube formation, indices of angiogenesis. Considering their well-documented mechanosensitivity, functional inter-dependence, and involvement in angiogenesis, we hypothesized roles for matrix metalloproteinases (MMP-2/9), RGD-dependent integrins, and urokinase plasminogen activator (uPA) in this process. BAECs were exposed to equibiaxial cyclic strain (5% strain, 1Hz for 24h) before their migration and tube formation was assessed by transwell migration and collagen gel tube formation assays, respectively. In response to strain, both migration and tube formation were increased by 1.83+/-0.1- and 1.84+/-0.1-fold, respectively. Pertussis toxin, a Gi-protein inhibitor, decreased strain-induced migration by 45.7+/-32% and tube formation by 69.8+/-13%, whilst protein tyrosine kinase (PTK) inhibition with genistein had no effect. siRNA-directed attenuation of endothelial MMP-9 (but not MMP-2) expression/activity decreased strain-induced migration and tube formation by 98.6+/-41% and 40.7+/-31%, respectively. Finally, integrin blockade with cRGD peptide and siRNA-directed attenuation of uPA expression reduced strain-induced tube formation by 85.7+/-15% and 84.7+/-31%, respectively, whilst having no effect on migration. CONCLUSIONS Cyclic strain promotes BAEC migration and tube formation in a Gi-protein-dependent PTK-independent manner. Moreover, we demonstrate for the first time a putative role for MMP-9 in both strain-induced events, whilst RGD-dependent integrins and uPA appear only to be involved in strain-induced tube formation.
Collapse
|
|
41
|
Soula-Rothhut M, Coissard C, Sartelet H, Boudot C, Bellon G, Martiny L, Rothhut B. The tumor suppressor PTEN inhibits EGF-induced TSP-1 and TIMP-1 expression in FTC-133 thyroid carcinoma cells. Exp Cell Res 2005; 304:187-201. [PMID: 15707585 DOI: 10.1016/j.yexcr.2004.10.026] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2004] [Revised: 10/29/2004] [Accepted: 10/30/2004] [Indexed: 11/26/2022]
Abstract
Thrombospondin-1 (TSP-1) is a multidomain extracellular macromolecule that was first identified as natural modulator of angiogenesis and tumor growth. In the present study, we found that epidermal growth factor (EGF) up-regulated TSP-1 expression in FTC-133 (primary tumor) but not in FTC-238 (lung metastasis) thyroid cancer cells. Both EGF and TSP-1 induced expression of tissue inhibitor of metalloproteinase-1 (TIMP-1) in a mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) and phosphatidylinositol 3-kinase (PI3-kinase)-dependent manner. In FTC-133 cells, EGF induced proliferation in a TSP-1- and TIMP-1-dependent manner. In addition, we determined that re-expression of the tumor suppressor protein PTEN induced cell death, an effect that correlated with a block of Akt kinase phosphorylation. EGF-induced TSP-1 and TIMP-1 promoter activity and protein expression were inhibited in FTC-133 cells stably expressing wtPTEN but not in cells expressing mutant PTEN. Furthermore, we found that wtPTEN inhibited EGF--but not TSP-1--stimulated FTC-133 cell migration and also inhibited invasion induced by EGF and by TSP-1. Finally, an antibody against TSP-1 reversed EGF-stimulated FTC-133 cell invasion as well as the constitutive invasive potential of FTC-238 cells. Overall, our results suggest that PTEN can function as an important modulator of extracellular matrix proteins in thyroid cancer. Therefore, analyzing differential regulation of TSP-1 by growth factors such as EGF can be helpful in understanding thyroid cancer development.
Collapse
Affiliation(s)
- Mahdhia Soula-Rothhut
- Unité Matrice Extracellulaire et Régulations Cellulaires, CNRS UMR 6198, Laboratory of Biochemistry, University of Reims Champagne-Ardenne, Moulin de la Housse, 51687 Reims Cedex 2, France
| | | | | | | | | | | | | |
Collapse
|
|
42
|
Zhou J, Rothman VL, Sargiannidou I, Dimitrov S, Qiu C, Smith E, Sheffield J, Sharma M, Tuszynski GP. Cloning and characterization of angiocidin, a tumor cell binding protein for thrombospondin-1. J Cell Biochem 2004; 92:125-46. [PMID: 15095410 DOI: 10.1002/jcb.20076] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
Thrombospondin-1 (TSP-1) is a matrix protein that has been implicated in mechanisms of tumor progression. Our laboratory previously showed that the CSVTCG (cys-ser-val-thr-cys-gly) sequence of TSP-1 functioned as a tumor cell adhesion domain and CSVTCG peptides as well as an anti-peptide antibody possessed anti-metastatic activity in a murine model of lung metastasis. In a subsequent study, a putative TSP-1 binding protein from lung carcinoma was isolated by CSVTCG-peptide affinity chromatography. In this study, we present the full-length cDNA of this binding protein isolated from a prostate cancer cell (PC3-NI) cDNA library. The purified recombinant protein, termed angiocidin, is a potent inhibitor of tumor growth of Lewis Lung carcinoma in vivo and tumor invasion and angiogenesis in vitro. In addition, the recombinant protein inhibits tumor and endothelial cell proliferation and induces apoptosis. The activity of angiocidin both in vivo and in vitro is partially dependent on its TSP-1 binding activity, since an angiocidin deletion mutant missing a high affinity-binding site for TSP-1 failed to inhibit tumor growth in vivo and was less active in its anti-tumor and anti-angiogenic activities in vitro. These results suggest that the anti-tumor activity of TSP-1 reported in many studies may be mediated in part by binding proteins such as angiocidin. Such proteins may function as tumor-suppressor proteins, which limit the growth of tumors by inhibiting angiogenesis and cell matrix interaction.
Collapse
Affiliation(s)
- Jing Zhou
- Temple University, Center for Neurovirology and Cancer Biology, 354 Biology Life Sciences Building (015-96), 1900 North 12th Street, Philadelphia, Pennsylvania 19122, USA
| | | | | | | | | | | | | | | | | |
Collapse
|
|
43
|
Morelli C, Campioni K, Parolin C, Palù G, Tognon M. Activity of the matrix metalloproteinase-9 promoter in human normal and tumor cells. J Cell Physiol 2004; 199:126-33. [PMID: 14978741 DOI: 10.1002/jcp.10450] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Matrix metalloproteinases (MMPs) belong to a family of proteins essential for those processes involving extracellular matrix degradation, such as embryonic development, morphogenesis, and tissue resorption and remodeling. Some members of this family play a crucial role also in tumor invasion. Most notably, MMP-9 is expressed in invasive tumors, and represents a key protein in brain tumor progression, whereas it is not expressed in adult normal tissues. The expression of the MMP-9, like other members of the family, is transcriptionally regulated. We, therefore, postulated that the MMP-9 promoter could be useful in driving selective expression of exogenous genes in tumor cells. This represents a key feature for gene therapy applications, since currently employed viral promoters induce severe organ toxicity, limiting the clinical benefits. In this study, we investigated the activity of the MMP-9 promoter in driving exogenous gene expression in human cell lines. High levels of reporter gene expression were detected in tumor derived cell lines, whereas the MMP-9 promoter activity in non-tumor cells was negligible. Furthermore, we show that tumor necrosis factor alpha (TNFalpha) is able to enhance considerably the MMP-9 promoter activity only in tumor cells. Since recent studies have indicated that MMP-9 enzymatic activity is detectable in the blood, it would be possible to screen potential responsive patients for a tumor gene therapy approach based on the MMP-9 promoter. Taken together these data suggest that MMP-9 promoter has the characteristics for transcritpionally targeted and inducible gene therapy applications.
Collapse
Affiliation(s)
- Cristina Morelli
- Department of Morphology and Embryology, and Center of Biotechnology, University of Ferrara, Ferrara, Italy
| | | | | | | | | |
Collapse
|
|
44
|
Donnini S, Morbidelli L, Taraboletti G, Ziche M. ERK1-2 and p38 MAPK regulate MMP/TIMP balance and function in response to thrombospondin-1 fragments in the microvascular endothelium. Life Sci 2004; 74:2975-85. [PMID: 15051421 DOI: 10.1016/j.lfs.2003.09.075] [Citation(s) in RCA: 40] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2003] [Accepted: 09/11/2003] [Indexed: 11/25/2022]
Abstract
We found that thrombospondin-1 (TSP-1) has opposite functions on angiogenesis depending on the nature of the proteolytic fragment released in vivo by the action of proteases. We studied the effect of the 25 and 140 kDa fragments of TSP-1 generated by its proteolytic cleavage on the cascade of mitogen activated protein kinase (MAPK) activation and matrix-metalloproteinase (MMP)/tissue inhibitor of metalloproteinase (TIMP) function and expression in microvascular endothelium. Post-capillary endothelial cells (CVEC) isolated from bovine heart were used. The 25 kDa fragment enhanced the upregulation of MMP-2 and -9 and reduced TIMP-2 expression leading to CVEC chemoinvasion. Conversely, the 140 kDa fragment blocked MMP-2 and -9 stimulation and doubled TIMP-2 expression, leading to inhibition of endothelial chemoinvasion induced by fibroblast growth factor-2 (FGF-2). MAPK activity (ERK1-2) was induced by TSP-1 and by the 25 kDa fragment, but not by the 140 kDa fragment which, however, promoted MAPK p38 activation. This evidence indicates that fragments originating from TSP-1 switch the pro- or anti-angiogenic phenotype in endothelium by targeting MAPK cascades with opposite functions on MMP/TIMP balance.
Collapse
Affiliation(s)
- Sandra Donnini
- Department of Molecular Biology, University of Siena, Via Aldo Moro, 2, 53100 Siena, Italy
| | | | | | | |
Collapse
|
|
45
|
Xiao Y, Kleeff J, Guo J, Gazdhar A, Liao Q, Di Cesare PE, Büchler MW, Friess H. Cartilage oligomeric matrix protein expression in hepatocellular carcinoma and the cirrhotic liver. J Gastroenterol Hepatol 2004; 19:296-302. [PMID: 14748877 DOI: 10.1111/j.1440-1746.2003.03268.x] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
BACKGROUND Cartilage oligomeric matrix protein (COMP) is the fifth member of the thrombospondin family of extracellular, calcium-binding proteins. It was initially isolated and characterized in cartilage tissue, where it is thought to contribute to the extracellular matrix composition and cell-extracellular matrix interaction. In the present study the expression of COMP was investigated in normal liver (n=19), liver cirrhosis (n=14) and hepatocellular carcinoma (HCC; n=16) tissues, both at the mRNA and protein level. METHODS AND RESULTS By northern blot and western blot analysis, COMP was absent or rarely expressed in the normal liver and liver cirrhosis tissues, but significantly overexpressed in HCC tissue samples. The COMP mRNA overexpression in HCC was not related to the clinical stage or tumor grade. By in situ hybridization and immunohistochemistry analysis, COMP mRNA and protein expression were localized within the cytoplasm of the tumor cells. CONCLUSION COMP is highly expressed within the tumor cells of HCC, suggesting that COMP might play a role in the pathophysiology of this disease.
Collapse
Affiliation(s)
- Yi Xiao
- Department of General Surgery, University of Heidelberg, Heidelberg, Germany
| | | | | | | | | | | | | | | |
Collapse
|
|
46
|
Li Y, Sarkar FH. Down-regulation of invasion and angiogenesis-related genes identified by cDNA microarray analysis of PC3 prostate cancer cells treated with genistein. Cancer Lett 2002; 186:157-64. [PMID: 12213285 DOI: 10.1016/s0304-3835(02)00349-x] [Citation(s) in RCA: 90] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Prostate cancer is the second leading cause of cancer related deaths in men in the United States and for many years the treatment results for metastatic prostate cancer have been disappointing. Our previous studies have shown that genistein elicits pleiotropic effects on prostate cancer cells; however, its role in invasion and metastasis has not been fully elucidated. In order to better understand the precise molecular mechanism(s) by which genistein exerts its effects on PC3 cells, we have utilized cDNA microarray to interrogate 12558 known genes to determine the gene expression profile altered by genistein treatment. We found a total of 832 genes which showed >2-fold change after genistein treatment. Among these genes, we found down-regulation of 11 genes (MMP-9, protease M, uPAR, VEGF, neuropilin, TSP, BPGF, LPA, TGF-beta2, TSP-1, PAR-2) and up-regulation of two genes (connective tissue growth factor, connective tissue activation peptide), which are related to angiogenesis, tumor cell invasion and metastasis. Reverse transcription-polymerase chain reaction, Western blot, and zymographic analysis were conducted to confirm the data of microarray at the level of mRNA, protein, and biological function. The results were in direct agreement with the microarray data. From these results, we conclude that genistein down-regulates the transcription and translation of genes critically involved in the control of angiogenesis, tumor cell invasion and metastasis, suggesting the possible therapeutic role of genistein for metastatic prostate cancer. Thus, genistein-induced alternations of gene expressions may be exploited for devising chemopreventive or therapeutic strategies, particularly for chemosensitization of metastatic prostate cancer to existing chemotherapeutic agents.
Collapse
Affiliation(s)
- Yiwei Li
- Department of Pathology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI 48201, USA
| | | |
Collapse
|
|
47
|
Abstract
Our previous studies have shown that genistein inhibits the growth of PC3 prostate cancer cells and induces apoptosis by inhibiting nuclear factor kappaB (NF-kappaB) and Akt signaling pathways. To better understand the precise molecular mechanism(s) by which genistein exerts its effects on PC3 cells, we utilized cDNA microarray to interrogate 12,558 known genes to determine the gene expression profiles altered by genistein treatment. We found a total of 832 genes that showed a greater than twofold change after genistein treatment from two independent experiments with a high degree of concordance. Among these genes, 774 genes were down-regulated and 58 genes were up-regulated with genistein treatment. Cluster analysis showed nine different types of expression alternations. These genes were also subjected to cluster analysis according to their biological functions. We found that genistein regulated the expression of genes that are critically involved in the regulation of cell growth, cell cycle, apoptosis, cell signaling transduction, angiogenesis, tumor cell invasion and metastasis. Reverse transcription-polymerase chain reaction (RT-PCR) analysis was used to confirm the results of cDNA microarray, and the results of RT-PCR were consistent with the microarray data. We conclude that genistein affected the expression of a large number of genes that are related to the control of cell survival and physiologic behaviors. The gene expression profiles provide comprehensive molecular mechanism(s) by which genistein exerts its pleiotropic effects on cancer cells. Genistein-induced regulation of these genes may be further exploited for devising chemopreventive and/or therapeutic strategies for prostate cancer.
Collapse
Affiliation(s)
- Yiwei Li
- Department of Pathology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, USA
| | | |
Collapse
|