Clinical, Cellular, and Molecular Aspects of Cancer Invasion

2003 ◽  
Vol 83 (2) ◽  
pp. 337-376 ◽  
Author(s):  
Marc Mareel ◽  
Ancy Leroy
Keyword(s):  
Cancer Cells ◽  
Cross Talk ◽  
Tyrosine Kinases ◽  
Molecular Mechanisms ◽  
Platelet Activating Factor ◽  
Tumor Development ◽  
Genetic Alterations ◽  
Small Gtpases ◽  
Small Gtpase ◽  
Host Cells

Invasion causes cancer malignancy. We review recent data about cellular and molecular mechanisms of invasion, focusing on cross-talk between the invaders and the host. Cancer disturbs these cellular activities that maintain multicellular organisms, namely, growth, differentiation, apoptosis, and tissue integrity. Multiple alterations in the genome of cancer cells underlie tumor development. These genetic alterations occur in varying orders; many of them concomitantly influence invasion as well as the other cancer-related cellular activities. Examples discussed are genes encoding elements of the cadherin/catenin complex, the nonreceptor tyrosine kinase Src, the receptor tyrosine kinases c-Met and FGFR, the small GTPase Ras, and the dual phosphatase PTEN. In microorganisms, invasion genes belong to the class of virulence genes. There are numerous clinical and experimental observations showing that invasion results from the cross-talk between cancer cells and host cells, comprising myofibroblasts, endothelial cells, and leukocytes, all of which are themselves invasive. In bone metastases, host osteoclasts serve as targets for therapy. The molecular analysis of invasion-associated cellular activities, namely, homotypic and heterotypic cell-cell adhesion, cell-matrix interactions and ectopic survival, migration, and proteolysis, reveal branching signal transduction pathways with extensive networks between individual pathways. Cellular responses to invasion-stimulatory molecules such as scatter factor, chemokines, leptin, trefoil factors, and bile acids or inhibitory factors such as platelet activating factor and thrombin depend on activation of trimeric G proteins, phosphoinositide 3-kinase, and the Rac and Rho family of small GTPases. The role of proteolysis in invasion is not limited to breakdown of extracellular matrix but also causes cleavage of proinvasive fragments from cell surface glycoproteins.

scholarly journals Structural basis for activation of trimeric Gi proteins by multiple growth factor receptors via GIV/Girdin

2014 ◽  
Vol 25 (22) ◽  
pp. 3654-3671 ◽  
Author(s):  
Changsheng Lin ◽  
Jason Ear ◽  
Krishna Midde ◽  
Inmaculada Lopez-Sanchez ◽  
Nicolas Aznar ◽  
...  
Keyword(s):  
Growth Factor ◽  
G Proteins ◽  
Protein Interaction ◽  
Cross Talk ◽  
Tyrosine Kinases ◽  
Molecular Mechanisms ◽  
Growth Factor Receptors ◽  
Structural Basis ◽  
Nucleotide Exchange ◽  
Protein Protein Interaction

A long-standing issue in the field of signal transduction is to understand the cross-talk between receptor tyrosine kinases (RTKs) and heterotrimeric G proteins, two major and distinct signaling hubs that control eukaryotic cell behavior. Although stimulation of many RTKs leads to activation of trimeric G proteins, the molecular mechanisms behind this phenomenon remain elusive. We discovered a unifying mechanism that allows GIV/Girdin, a bona fide metastasis-related protein and a guanine-nucleotide exchange factor (GEF) for Gαi, to serve as a direct platform for multiple RTKs to activate Gαi proteins. Using a combination of homology modeling, protein–protein interaction, and kinase assays, we demonstrate that a stretch of ∼110 amino acids within GIV C-terminus displays structural plasticity that allows folding into a SH2-like domain in the presence of phosphotyrosine ligands. Using protein–protein interaction assays, we demonstrated that both SH2 and GEF domains of GIV are required for the formation of a ligand-activated ternary complex between GIV, Gαi, and growth factor receptors and for activation of Gαi after growth factor stimulation. Expression of a SH2-deficient GIV mutant (Arg 1745→Leu) that cannot bind RTKs impaired all previously demonstrated functions of GIV—Akt enhancement, actin remodeling, and cell migration. The mechanistic and structural insights gained here shed light on the long-standing questions surrounding RTK/G protein cross-talk, set a novel paradigm, and characterize a unique pharmacological target for uncoupling GIV-dependent signaling downstream of multiple oncogenic RTKs.

scholarly journals Widespread alteration of protein autoinhibition in human cancers

2018 ◽  
Author(s):  
Ashwani Jha ◽  
Jennifer M. Bui ◽  
Dokyun Na ◽  
Jörg Gsponer
Keyword(s):  
Cancer Cells ◽  
Molecular Mechanisms ◽  
Signal Propagation ◽  
Genetic Alterations ◽  
Missense Mutations ◽  
Pathway Activation ◽  
Tumorigenic Potential ◽  
Significant Enrichment ◽  
Cancer Types ◽  
Cancer Drivers

ABSTRACTAutoinhibition is a prevalent allosteric regulatory mechanism in signaling proteins as it prevents spurious pathway activation and primes for signal propagation only under appropriate inputs. Altered functioning of inhibitory allosteric switches underlies the tumorigenic potential of numerous cancer drivers. However, whether protein autoinhibition is altered generically in cancer cells remains elusive. Here, we reveal that cancer-associated missense mutations and fusion breakpoints are found with significant enrichment within inhibitory allosteric switches across all cancer types, which in the case of the fusion breakpoints is specific to cancer and not present in other diseases. Recurrently disrupted or mutated allosteric switches identify established and new cancer drivers. Cancer-specific mutations in allosteric switches are associated with distinct changes in signaling, and suggest molecular mechanisms for altered protein regulation, which in the case of ASK1, DAPK2 and EIF4G1 were supported by biophysical simulations. Our results demonstrate that autoinhibition-modulating genetic alterations are positively selected for by cancer cells, and that their study provides valuable insights into molecular mechanisms of cancer misregulation.

scholarly journals Granulocyte CEACAM3 Is a Phagocytic Receptor of the Innate Immune System that Mediates Recognition and Elimination of Human-specific Pathogens

2004 ◽  
Vol 199 (1) ◽  
pp. 35-46 ◽  
Author(s):  
Tim Schmitter ◽  
Franziska Agerer ◽  
Lisa Peterson ◽  
Petra Münzner ◽  
Christof R. Hauck
Keyword(s):  
Immune System ◽  
Tyrosine Kinases ◽  
Innate Immune System ◽  
Small Gtpase ◽  
Innate Immune ◽  
Dominant Negative ◽  
Host Cells ◽  
Human Pathogens ◽  
Human Granulocytes ◽  
Human Specific

Carcinoembryonic antigen-related cell adhesion molecules (CEACAMs) are used by several human pathogens to anchor themselves to or invade host cells. Interestingly, human granulocytes express a specific isoform, CEACAM3, that participates together with CEACAM1 and CEACAM6 in the recognition of CEACAM-binding microorganisms. Here we show that CEACAM3 can direct efficient, opsonin-independent phagocytosis of CEACAM-binding Neisseria, Moraxella, and Haemophilus species. CEACAM3- but not CEACAM6-mediated uptake is blocked by dominant-negative versions of the small GTPase Rac. Moreover, CEACAM3 engagement triggers membrane recruitment and increased GTP loading of Rac that are not observed upon bacterial binding to CEACAM6. Internalization and Rac stimulation are also inhibited by compromising the integrity of an immunoreceptor tyrosine-based activation motif (ITAM)–like sequence in the cytoplasmic tail of CEACAM3 or by interference with Src family protein tyrosine kinases that phosphorylate CEACAM3. In contrast to interfering with CEACAM6, blockage of CEACAM3-mediated events reduces the ability of primary human granulocytes to internalize and eliminate CEACAM-binding bacteria, indicating an important role of CEACAM3 in the control of human-specific pathogens by the innate immune system.

Small GTPases and Brucella entry into the endoplasmic reticulum

2012 ◽  
Vol 40 (6) ◽  
pp. 1348-1352 ◽  
Author(s):  
Xavier de Bolle ◽  
Jean-Jacques Letesson ◽  
Jean-Pierre Gorvel
Keyword(s):  
Endoplasmic Reticulum ◽  
Pathogenic Bacteria ◽  
Wild Type Strain ◽  
Specific Interaction ◽  
Small Gtpases ◽  
Small Gtpase ◽  
Endocytic Pathway ◽  
Host Cells ◽  
Kinetics Of ◽  
Membrane Reservoir

A key determinant for intracellular pathogenic bacteria to ensure their virulence within host cells is their ability to bypass the endocytic pathway and to reach a safe niche of replication. In the case of Brucella, the bacterium targets the ER (endoplasmic reticulum) to create a replicating niche called the BCV (Brucella-containing vacuole). The ER is a suitable strategic place for pathogenic Brucella. Indeed, bacteria can be hidden from host cell defences to persist within the host, and they can take advantage of the membrane reservoir delivered by the ER to replicate. Interaction with the ER leads to the presence on the BCV of the GAPDH (glyceraldehyde-3-phosphate dehydrogenase) and the small GTPase Rab2 known to be located on secretory vesicles that traffic between the ER and the Golgi apparatus. GAPDH and the small GTPase Rab2 controls Brucella replication at late times post-infection. A specific interaction between the human small GTPase Rab2 and a Brucella spp. protein named RicA was identified. Altered kinetics of intracellular trafficking and faster proliferation of the Brucella abortus ΔricA mutant was observed compared with the wild-type strain. RicA is the first reported effector with a proposed function for B. abortus.

scholarly journals Hierarchies of Host Factor Dynamics at the Entry Site of Shigella flexneri during Host Cell Invasion

2012 ◽  
Vol 80 (7) ◽  
pp. 2548-2557 ◽  
Author(s):  
Soudeh Ehsani ◽  
José Carlos Santos ◽  
Cristina D. Rodrigues ◽  
Ricardo Henriques ◽  
Laurent Audry ◽  
...  
Keyword(s):  
Host Cell ◽  
Tyrosine Kinases ◽  
Time Course ◽  
Shigella Flexneri ◽  
Time Lapse ◽  
Small Gtpases ◽  
Host Factors ◽  
Host Cells ◽  
Entry Site ◽  
Content Type

ABSTRACTShigella flexneri, the causative agent of bacillary dysentery, induces massive cytoskeletal rearrangement, resulting in its entry into nonphagocytic epithelial cells. The bacterium-engulfing membrane ruffles are formed by polymerizing actin, a process activated through injected bacterial effectors that target host small GTPases and tyrosine kinases. Once inside the host cell,S. flexneriescapes from the endocytic vacuole within minutes to move intra- and intercellularly. We quantified the fluorescence signals from fluorescently tagged host factors that are recruited to the site of pathogen entry and vacuolar escape. Quantitative time lapse fluorescence imaging revealed simultaneous recruitment of polymerizing actin, small GTPases of the Rho family, and tyrosine kinases. In contrast, we found that actin surrounding the vacuole containing bacteria dispersed first from the disassembling membranes, whereas other host factors remained colocalized with the membrane remnants. Furthermore, we found that the disassembly of the membrane remnants took place rapidly, within minutes after bacterial release into the cytoplasm. Superresolution visualization of galectin 3 through photoactivated localization microscopy characterized these remnants as small, specular, patchy structures between 30 and 300 nm in diameter. Using our experimental setup to track the time course of infection, we identified theS. flexnerieffector IpgB1 as an accelerator of the infection pace, specifically targeting the entry step, but not vacuolar progression or escape. Together, our studies show that bacterial entry into host cells follows precise kinetics and that this time course can be targeted by the pathogen.

scholarly journals Aberrant Signaling Pathways in Sinonasal Intestinal-Type Adenocarcinoma

Cancers ◽  
2021 ◽  
Vol 13 (19) ◽  
pp. 5022
Author(s):  
Cristina Riobello ◽  
Paula Sánchez-Fernández ◽  
Virginia N. Cabal ◽  
Rocío García-Marín ◽  
Laura Suárez-Fernández ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Tyrosine Kinases ◽  
Wide Spectrum ◽  
Tumor Development ◽  
Gene Mutations ◽  
Genetic Alterations ◽  
Activity Level ◽  
Intestinal Type ◽  
Specific Gene ◽  
Intestinal Type Adenocarcinoma

Sinonasal intestinal-type adenocarcinoma (ITAC) is strongly related to occupational exposure to wood and leather dust, however, little is known on the genetic alterations involved in tumor development and progression. The aim of this study was to identify tumorigenic signaling pathways affected by gene mutations and their relation to clinical features. We applied whole exome sequencing of 120 cancer-related genes in 50 ITACs and analyzed the signaling activity of four specific pathways frequently affected by mutations. Genes involved in DNA damage response showed somatic mutations in 30% of cases, including four tumors that also harbored germline mutations. Genes in Wnt, MAPK and PI3K pathways harbored mutations in 20%, 20% and 24% of cases, respectively. Mutations and copy number gains in receptor tyrosine kinases possibly affecting MAPK and PI3K pathways occurred in 44% of cases. Expression of key pathway proteins showed no correlation to mutations in these pathways, except for nuclear β-catenin and APC/CTNNB1 mutation. No specific gene mutation, mutated pathway, nor pathway activity level showed correlation to clinical data or survival. In addition, a similar mutational profile was observed among histological subtypes. The wide spectrum of gene mutations suggests that ITAC is a genetically heterogeneous without specific characterizing gene mutations.

scholarly journals Regulation of antitumor immunity by inflammation-induced epigenetic alterations

2021 ◽  
Author(s):  
Michael Karin ◽  
Shabnam Shalapour
Keyword(s):  
Cancer Cells ◽  
Chronic Inflammation ◽  
Antitumor Immunity ◽  
Immune Escape ◽  
Tumor Development ◽  
Treatment Resistance ◽  
Genetic Alterations ◽  
Cancer Development ◽  
Epigenetic Alterations ◽  
Regulatory Processes

AbstractChronic inflammation promotes tumor development, progression, and metastatic dissemination and causes treatment resistance. The accumulation of genetic alterations and loss of normal cellular regulatory processes are not only associated with cancer growth and progression but also result in the expression of tumor-specific and tumor-associated antigens that may activate antitumor immunity. This antagonism between inflammation and immunity and the ability of cancer cells to avoid immune detection affect the course of cancer development and treatment outcomes. While inflammation, particularly acute inflammation, supports T-cell priming, activation, and infiltration into infected tissues, chronic inflammation is mostly immunosuppressive. However, the main mechanisms that dictate the outcome of the inflammation-immunity interplay are not well understood. Recent data suggest that inflammation triggers epigenetic alterations in cancer cells and components of the tumor microenvironment. These alterations can affect and modulate numerous aspects of cancer development, including tumor growth, the metabolic state, metastatic spread, immune escape, and immunosuppressive or immunosupportive leukocyte generation. In this review, we discuss the role of inflammation in initiating epigenetic alterations in immune cells, cancer-associated fibroblasts, and cancer cells and suggest how and when epigenetic interventions can be combined with immunotherapies to improve therapeutic outcomes.

Impact of the FcγII-receptor on quartz uptake and inflammatory response by alveolar macrophages

2008 ◽  
Vol 294 (6) ◽  
pp. L1137-L1148 ◽  
Author(s):  
Petra Haberzettl ◽  
Roel P. F. Schins ◽  
Doris Höhr ◽  
Verena Wilhelmi ◽  
Paul J. A. Borm ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Alveolar Macrophages ◽  
Tyrosine Kinases ◽  
Molecular Mechanisms ◽  
Morphological Changes ◽  
Inhibitory Effect ◽  
Small Gtpases ◽  
Downstream Signaling ◽  
Particle Uptake

The inflammatory response following particle inhalation is described as a key event in the development of lung diseases, e.g., fibrosis and cancer. The essential role of alveolar macrophages (AM) in the pathogenicity of particles through their functions in lung clearance and mediation of inflammation is well known. However, the molecular mechanisms and direct consequences of particle uptake are still unclear. Inhibition of different classic phagocytosis receptors by flow cytometry shows a reduction of the dose-dependent quartz particle (DQ12) uptake in the rat AM cell line NR8383. Thereby the strongest inhibitory effect was observed by blocking the FcγII-receptor (FcγII-R). Fluorescence immunocytochemistry, demonstrating FcγII-R clustering at particle binding sites as well as transmission electron microscopy, visualizing zippering mechanism-like morphological changes, confirmed the role of the FcγII-R in DQ12 phagocytosis. FcγII-R participation in DQ12 uptake was further strengthened by the quartz-induced activation of the Src-kinase Lyn, the phospho-tyrosine kinases Syk (spleen tyrosine kinase) and PI3K (phosphatidylinositol 3-kinase), as shown by Western blotting. Activation of the small GTPases Rac1 and Cdc42, shown by immunoprecipitation, as well as inhibition of tyrosine kinases, GTPases, or Rac1 provided further support for the role of the FcγII-R. Consistent with the uptake results, FcγII-R activation with its specific ligand caused a similar generation of reactive oxygen species and TNF-α release as observed after treatment with DQ12. In conclusion, our results indicate a major role of FcγII-R and its downstream signaling cascade in the phagocytosis of quartz particles in AM as well as in the associated generation and release of inflammatory mediators.

scholarly journals ID:2037 Molecular mechanisms underlying resistance to MEK1/2 inhibitor in BRAF-mutated colorectal cancer

2017 ◽  
Vol 4 (S) ◽  
pp. 68
Author(s):  
Hong-Quan Duong
Keyword(s):  
Colorectal Cancer ◽  
Cancer Cells ◽  
Molecular Mechanisms ◽  
Acquired Resistance ◽  
Genetic Alterations ◽  
Scaffold Protein ◽  
Colorectal Carcinomas ◽  
Intrinsic Resistance ◽  
Oncogenic Signaling ◽  
Colorectal Cancer Cells

Colorectal carcinomas are characterized by multiple genetic alterations, including constitutive Wnt activity and gain-of-function mutations in K-RAS and B-RAF. BRAF encodes a Ser/Thr kinase acting in the Ras/MEK/ERK pathway and the V600E mutation found in 11% of colorectal cancers renders this kinase constitutively active. B-RAF mutated colorectal carcinomas represents a very aggressive entity with a poor prognosis. Understanding the molecular mechanisms activated downstream of mutated B-RAF is urgently needed to design new therapeutic avenues to treat B-ARF mutated colorectal carcinomas and to circumvent resistance to therapies targeting the Ras/Raf/MEK1/ERK1/2 pathway. In a search for candidates that critically contribute to both intrinsic and acquired resistance to MEK1 inhibition in B-RAF mutated colorectal cancer cells, we identified one scaffold protein whose expression is driven by both NF-kB and AP-1 families of transcription factors. This scaffold protein promotes the expression of HER2 and HER3 in colorectal cancer cells subjected to MEK1 or B-RAF inhibition (Selumetinib and Vemurafenib, respectively) and, as such, is critically involved in the intrinsic resistance to these targeted therapies. The same scaffold protein is also strongly induced in B-RAF but not K-RAS mutated colorectal cancer cells showing acquired resistance to MEK1 inhibition. Interfering with the expression of this scaffold protein circumvents both intrinsic and acquired resistance to Selumetinib in B-RAF mutated colorectal cancer cells. Our study defines a new molecular actor critically involved in oncogenic signaling pathways triggered by mutated B-RAF. Our study also defineS new combinatory therapies to better treat B-RAF-mutated colorectal carcinomas.

scholarly journals Receptor tyrosine kinases as a therapeutic target by natural compounds in cancer treatment

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Toheeb A. Balogun ◽  
Oluwasegun M. Ige ◽  
Abdullahi O. Alausa ◽  
Chijioke O. Onyeani ◽  
Zainab A. Tiamiyu ◽  
...  
Keyword(s):  
Growth Factor ◽  
Cancer Cells ◽  
Tyrosine Kinases ◽  
Molecular Mechanisms ◽  
Receptor Tyrosine Kinases ◽  
Clinical Manifestations ◽  
Natural Compounds ◽  
In Vivo Studies ◽  
Tyrosine Kinase Domain ◽  
Main Body

Abstract Background Receptor tyrosine kinases (RTKs) are single-pass transmembrane proteins that play significant roles in regulating cellular processes, including cell division and growth. Overexpression and mutations of RTKs have been found in clinical manifestations of different forms of cancer. Therefore, RTKs have received considerable interest as a therapeutic biomarker in the treatment of cancer cells. Main body of the abstract Comprehensive data on RTKs, pharmacological and biological properties of natural compounds were systematically searched up to 2021 using relevant keywords from various databases, such as Google Scholar, PubMed, Web of Science, and Scopus. The scientific search by various standard electronic resources and databases unveils the effectiveness of medicinal plants in the treatment of various cancers. In vitro and in vivo studies suggested that bioactive compounds such as flavonoids, phenols, alkaloids, and many others can be used pharmacologically as RTKs inhibitors (RTKI) either by competing with ATP at the ATP binding site of the tyrosine kinase domain or competing for the receptor extracellular domain. Additionally, studies conducted on animal models indicated that inhibition of RTKs catalytic activity by natural compounds is one of the most effective ways to block the activation of RTKs signaling cascades, thereby hampering the proliferation of cancer cells. Furthermore, various pharmacological experiments, transcriptomic, and proteomic data also reported that cancer cells treated with different plants extracts or isolated phytochemicals exhibited better anticancer properties with minimal side effects than synthetic drugs. Clinically, natural compounds have demonstrated significant anti-proliferative effect via induction of cell apoptosis in cancer cell lines. Short conclusion An in-depth knowledge of the mechanism of inhibition and structural characterization of RTKs is important to the design of novel and selective RTKIs. This review focuses on the molecular mechanisms and structures of natural compounds RTKI targeting vascular endothelial growth factor, epidermal growth factor receptor, insulin receptor, and platelet-derived growth factor while also giving future directions to ameliorate the scientific burden of cancer. Graphic abstract

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