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Integrins and Their Extracellular Matrix Ligands in Lymphangiogenesis and Lymph Node Metastasis  [PDF]
Jie Chen,J. Steven Alexander,A. Wayne Orr
International Journal of Cell Biology , 2012, DOI: 10.1155/2012/853703
Abstract: In the 1970s, the late Judah Folkman postulated that tumors grow proportionately to their blood supply and that tumor angiogenesis removed this limitation promoting growth and metastasis. Work over the past 40 years, varying from molecular examination to clinical trials, verified this hypothesis and identified a host of therapeutic targets to limit tumor angiogenesis, including the integrin family of extracellular matrix receptors. However, the propensity for some tumors to spread through lymphatics suggests that lymphangiogenesis plays a similarly important role. Lymphangiogenesis inhibitors reduce lymph node metastasis, the leading indicator of poor prognosis, whereas inducing lymphangiogenesis promotes lymph node metastasis even in cancers not prone to lymphatic dissemination. Recent works highlight a role for integrins in lymphangiogenesis and suggest that integrin inhibitors may serve as therapeutic targets to limit lymphangiogenesis and lymph node metastasis. This review discusses the current literature on integrin-matrix interactions in lymphatic vessel development and lymphangiogenesis and highlights our current knowledge on how specific integrins regulate tumor lymphangiogenesis. 1. Introduction to the Lymphatic Circulation Blood vessels supply tissues with nutrients and oxygen, remove waste products, and provide a mechanism for leukocyte homing. Capillary exchange is vital for this process. As blood pressure causes fluid extravasation in the arterial side of the capillary bed, colloid osmotic pressure drives resorption of the fluid on the venous side. However, ~10% of this fluid is retained in the tissue accumulating as interstitial fluid [1]. During inflammation and tumorigenesis, this accumulation of interstitial fluid is augmented due to enhanced permeability of the capillaries resulting in tissue edema [2]. The lymphatic system regulates the transfer of interstitial fluid and cells from the tissue back into the circulation [1]. Nearly all vascularized tissues contain lymphatics with the exception of the bone marrow, retina, and brain [3, 4]. Disrupting lymphatic vessel function, due to either primary (genetic) or secondary (infectious, vessel damage) mechanisms, causes chronic tissue edema. In addition to fluid transport, the lymphatic circulation plays a vital role in the inflammatory response. Antigen-presenting cells such as macrophages and dendritic cells encounter antigen at sites of local tissue inflammation. Endothelial cells in the lymphatic capillaries produce CCL21 [5], a chemokine that stimulates antigen-presenting cells to
Increased expression of integrin-linked kinase is associated with shorter survival in non-small cell lung cancer
Iwao Takanami
BMC Cancer , 2005, DOI: 10.1186/1471-2407-5-1
Abstract: We investigated ILK expression in patients with NSCLC by means of immunohistochemistry.ILK expression was significantly associated with tumor grade, T status, lymph node metastasis and stage. (p = 0.0169 for tumor grade; p = 0.0006 for T status; p = 0.0002 for lymph node metastasis; p < 0.0001 for stage). The 5-year survival rates for patients with strong and weak or no ILK expression levels were 20% and 59%, respectively: the difference was statistically significant (p < 0.0001). A multivariate analysis of survival revealed that ILK expression, T status, N status and vascular invasion were statistically significant prognostic factors (p = 0.0218 for ILK; p = 0.0046 for T status; p < 0.0001 for N status; p < 0.0001 for vascular invasion).Our study demonstrates that increased expression of ILK is a poor prognostic factor in patients with NSCLC.Interaction of cells with the extracellular matrix regulates many physiological and pathological processes. These interactions are mediated by a large family of cell surface receptors known as integrins, which recognize several extracellular matrix proteins, including fibronectin, collagens, and vitronectin [1]. Integrins act as the bridge between extracellular matrix components and the cytoskeleton and other proteins, regulating cell survival, proliferation, differentiation, and migration [1]. Integrins are important mediators of tumor invasion and metastasis through interaction with extracellular matrix. All integrins are heterodimers composed of one copy each of two subunits, α and β. Many studies examined the association between integrins and clinicalpathology or prognosis in lung cancer. Reduced integrin α3β1 expression was reported to be a factor of poor prognosis in pulmonary adenocarcinoma [2]. Increased expression of integrin β1 was reported to be a poor prognosis in small cell lung cancer [3]. Integrin α5β1 was reported to be associated with lymph node metastasis of non-small cell lung cancer (NSCLC) [4], or to be a p
Integrins and extracellular matrix in mechanotransduction
Ramage L
Cell Health and Cytoskeleton , 2012, DOI: http://dx.doi.org/10.2147/CHC.S21829
Abstract: tegrins and extracellular matrix in mechanotransduction Review (2543) Total Article Views Authors: Ramage L Published Date December 2011 Volume 2012:4 Pages 1 - 9 DOI: http://dx.doi.org/10.2147/CHC.S21829 Lindsay Ramage Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, UK Abstract: Integrins are a family of cell surface receptors which mediate cell–matrix and cell–cell adhesions. Among other functions they provide an important mechanical link between the cells external and intracellular environments while the adhesions that they form also have critical roles in cellular signal-transduction. Cell–matrix contacts occur at zones in the cell surface where adhesion receptors cluster and when activated the receptors bind to ligands in the extracellular matrix. The extracellular matrix surrounds the cells of tissues and forms the structural support of tissue which is particularly important in connective tissues. Cells attach to the extracellular matrix through specific cell-surface receptors and molecules including integrins and transmembrane proteoglycans. Integrins work alongside other proteins such as cadherins, immunoglobulin superfamily cell adhesion molecules, selectins, and syndecans to mediate cell–cell and cell–matrix interactions and communication. Activation of adhesion receptors triggers the formation of matrix contacts in which bound matrix components, adhesion receptors, and associated intracellular cytoskeletal and signaling molecules form large functional, localized multiprotein complexes. Cell–matrix contacts are important in a variety of different cell and tissue properties including embryonic development, inflammatory responses, wound healing, and adult tissue homeostasis. This review summarizes the roles and functions of integrins and extracellular matrix proteins in mechanotransduction.
Integrins and extracellular matrix in mechanotransduction  [cached]
Ramage L
Cell Health and Cytoskeleton , 2011,
Abstract: Lindsay RamageQueen’s Medical Research Institute, University of Edinburgh, Edinburgh, UKAbstract: Integrins are a family of cell surface receptors which mediate cell–matrix and cell–cell adhesions. Among other functions they provide an important mechanical link between the cells external and intracellular environments while the adhesions that they form also have critical roles in cellular signal-transduction. Cell–matrix contacts occur at zones in the cell surface where adhesion receptors cluster and when activated the receptors bind to ligands in the extracellular matrix. The extracellular matrix surrounds the cells of tissues and forms the structural support of tissue which is particularly important in connective tissues. Cells attach to the extracellular matrix through specific cell-surface receptors and molecules including integrins and transmembrane proteoglycans. Integrins work alongside other proteins such as cadherins, immunoglobulin superfamily cell adhesion molecules, selectins, and syndecans to mediate cell–cell and cell–matrix interactions and communication. Activation of adhesion receptors triggers the formation of matrix contacts in which bound matrix components, adhesion receptors, and associated intracellular cytoskeletal and signaling molecules form large functional, localized multiprotein complexes. Cell–matrix contacts are important in a variety of different cell and tissue properties including embryonic development, inflammatory responses, wound healing, and adult tissue homeostasis. This review summarizes the roles and functions of integrins and extracellular matrix proteins in mechanotransduction.Keywords: ligand binding, α subunit, subunit, focal adhesion, cell differentiation, mechanical loading, cell–matrix interaction
Rab27 GTPases Distribute Extracellular Nanomaps for Invasive Growth and Metastasis: Implications for Prognosis and Treatment  [PDF]
An Hendrix,Olivier De Wever
International Journal of Molecular Sciences , 2013, DOI: 10.3390/ijms14059883
Abstract: The Rab27 family of small GTPases regulates exocytosis of distinct vesicle types including multivesicular endosomes, which results in the release of exosomes. Exosomes are nanometer-sized membrane vesicles that enclose soluble factors such as proteins and nucleic acids within a lipid bilayer and can travel toward distant tissues to influence multiple aspects of cell behavior. In our view that tumors are endocrine organs producing exosomes, Rab27 GTPases and their effector proteins are critical determinants for invasive growth and metastasis. Rab27 proteins and their effectors may serve as prognostic biomarkers or as targets for patient-tailored therapy.
Integrin expression profiling identifies integrin alpha5 and beta1 as prognostic factors in early stage non-small cell lung cancer
Anne-Marie C Dingemans, Vivian van den Boogaart, Bettine A Vosse, Robert-Jan van Suylen, Arjan W Griffioen, Victor L Thijssen
Molecular Cancer , 2010, DOI: 10.1186/1476-4598-9-152
Abstract: A retrospective study was performed on frozen primary tumors of 68 early stage non-small cell lung cancer patients with a follow up of at least 10 years. From all tumor tissues, RNA was isolated and reverse transcribed into cDNA. qPCR was used to generate mRNA expression profiles including integrins alpha1, 2, 3, 4, 5, 6, 7, 11, and V as well as integrins beta1, 3, 4, 5, 6, and 8.The expression levels of integrins alpha5, beta1 and beta3 predicted overall survival and disease free survival in early stage NSCLC patients. There was no association between integrin expression and lymph node metastases. Comparison between the histological subtypes revealed a distinct integrin signature for squamous cell carcinoma while the profiles of adenocarcinoma and large cell carcinoma were largely the same.Integrin expression in NSCLC is important for the development and behavior of the tumor and influences the survival of the patient. Determining the integrin expression profile might serve as a tool in predicting the prognosis of individual patients.Lung cancer is the most common cause of cancer related death in Europe, accounting for one-fifth of the total number of cancer deaths[1]. The prognosis of patients with non-small cell lung cancer (NSCLC), which constitutes 80% of all lung cancers, is poor, even in patients with early stage disease[2]. The five year survival rate of patients with resected NSCLC is between 50-60%, and 50-60% of patients will have disease recurrence within 2 years[3]. Recently, it has been shown that adjuvant chemotherapy improves overall and disease-free survival in patients with resected stage stage II-IIIa NSCLC, but not all patients benefit[3]. Thus, selection of patients with high risk of recurrence is warranted.An important predictor of poor prognosis in patients with NSCLC is early distant metastasis[2]. When cancer cells become metastatic, they develop altered affinity and avidity for the extracellular matrix (ECM). This phenotypic change is partl
RGD-Binding Integrins in Prostate Cancer: Expression Patterns and Therapeutic Prospects against Bone Metastasis  [PDF]
Mark Sutherland,Andrew Gordon,Steven D. Shnyder,Laurence H. Patterson,Helen M. Sheldrake
Cancers , 2012, DOI: 10.3390/cancers4041106
Abstract: Prostate cancer is the third leading cause of male cancer deaths in the developed world. The current lack of highly specific detection methods and efficient therapeutic agents for advanced disease have been identified as problems requiring further research. The integrins play a vital role in the cross-talk between the cell and extracellular matrix, enhancing the growth, migration, invasion and metastasis of cancer cells. Progression and metastasis of prostate adenocarcinoma is strongly associated with changes in integrin expression, notably abnormal expression and activation of the β 3 integrins in tumour cells, which promotes haematogenous spread and tumour growth in bone. As such, influencing integrin cell expression and function using targeted therapeutics represents a potential treatment for bone metastasis, the most common and debilitating complication of advanced prostate cancer. In this review, we highlight the multiple ways in which RGD-binding integrins contribute to prostate cancer progression and metastasis, and identify the rationale for development of multi-integrin antagonists targeting the RGD-binding subfamily as molecularly targeted agents for its treatment.
New tricks for metastasis-associated macrophages
Bin-Zhi Qian, Jeffrey W Pollard
Breast Cancer Research , 2012, DOI: 10.1186/bcr3143
Abstract: Metastasis is the major cause of breast cancer lethality. In target organs, a series of events are required for the establishment of metastatic tumor cells. These events include: adherence to the blood vessel, extravasation, survival, establishment of micrometastases, and persistent growth into macrometastases. While tumor cell intrinsic factors can enhance metastatic efficiency and site selection [1], metastasis also relies on interactions between spreading tumor cells and host factors in the target organ [2]. These host factors include cytokines/growth factors, extracellular matrix, platelets, and different stromal and immune cells [2]. Particularly, a population of metastasis-associated macrophages has been identified that promotes breast cancer metastasis [3]. These cells, derived from a subset of inflammatory monocytic precursor cells, promote tumor cell extravasation through vascular endothelial growth factor production and their subsequent survival and growth [3,4].Chen and colleagues have provided a new mechanism for the metastasis-promoting function of metastasis-associated macrophages through their adherence to tumor cells that provides survival signals to the tumor cells [5]. Previous studies from this group compared gene expression changes of subclones of a human mammary carcinoma cell line, MDA-MB-231, which have differential metastatic efficiencies to target organs when introduced into the circulation of immune-deficient mice [6]. The hypothesis being that certain genes are preferentially expressed by cells with higher metastatic efficiency and that if their expression is correlated with poor prognosis and metastatic disease, this gene is likely to contribute to the metastatic process in patients. Based on this idea, a lung metastasis gene expression signature was identified by comparing subclones selected for lung metastasis with the parental MDA-MB-231 line and those subclones selected for metastasis to bone or brain [6]. The focus of the current stu
Integrins and Oncogenes: Partners in Crime  [cached]
Jordi Carreras Puigvert,Louise von Stechow,Bob van de Water,Erik HJ Danen
Molecular and Cellular Pharmacology , 2009,
Abstract: Metastatic spread and acquired or intrinsic resistance to existing therapies form the two major obstacles in cancer treatment. Accumulating evidence indicates that cancer growth, metastasis, and the response to therapy are strongly affected by integrin-mediated interactions with the extracellular matrix (ECM) in the tumor microenvironment. Indeed, altered expression levels of various integrins has been associated with poor differentiation, increased metastasis, and decreased overall and recurrence-free survival after radio- or chemotherapy in different types of cancer. Recent evidence indicates that the role of specific integrins in cancer progression and treatment response depends on the spectrum of oncogenic mutations present in cancer cells. In this PharmSight, we discuss several examples of such cross talk between integrins and oncogenes that may point to new avenues for cancer therapy.
The integrins
Yoshikazu Takada, Xiaojing Ye, Scott Simon
Genome Biology , 2007, DOI: 10.1186/gb-2007-8-5-215
Abstract: The integrins are a superfamily of cell adhesion receptors that recognize mainly extracellular matrix ligands and cell-surface ligands, although some soluble ligands have been identified [1]. They are transmembrane αβ heterodimers, and at least 18 α and eight β subunits are known in humans [2] (Figure 1; lists of the integrin subunits present in mouse, chicken, zebrafish, Caenorhabditis elegans, Xenopus laevis and Drosophila melanogaster are given in Additional data file 1). Integrin α and β subunits are totally distinct, with no detectable homology between them; sequence identity among α subunits is about 30% and among β subunits 45%, indicating that both the α and the β gene families evolved by gene duplication (Figure 2). In humans, genes for both α and β subunits are located on various chromosomes. However, genes for integrins expressed in leukocytes (subunits αL, αM, αD, and αX) are clustered at 16p11, while for those expressed in platelets and endothelial cells, the αIIb and β3 genes are at 17q21.32, and the α6, α4, and αV cluster at 2q31 (Table 1). Some integrin ? subunits (?1, ?2, ?10, ?11, ?M, ?L, ?D, and ?X) contain a so-called I (insertion or interaction), or A, domain, while others do not. The I-domain integrin α subunits are closely related to each other (Figure 2a). Also closely related to each other are the family of non-I-domain α subunits that recognize the RGD motif (αV, α8, α5, and αIIb) and the family of laminin-binding α subunits (α3, α6, and α7). Studies on integrin genes from lower and higher eukaryotes clearly indicate that integrin genes (both α and β) derived from a common ancestral gene by gene duplications. A genomic analysis among 24 invertebrate and vertebrate species revealed that the α and β integrin structure, along with the inserted α I domain, has been highly conserved during the evolution of vertebrates [3].The crystal structures of human integrins αVβ3 [4,5] and αIIbβ3 [6] show that the extracellular portion of an integrin hetero
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