The cancer cell adhesion resistome: mechanisms, targeting and translational approaches

2017 ◽  
Vol 398 (7) ◽  
pp. 721-735 ◽  
Author(s):  
Ellen Dickreuter ◽  
Nils Cordes
Keyword(s):  
Cell Adhesion ◽  
Cancer Cells ◽  
Current Knowledge ◽  
Therapy Resistance ◽  
Adapter Proteins ◽  
Cancer Therapies ◽  
Synthetic Lethal ◽  
Cancer Cell Adhesion ◽  
Underlying Mechanisms ◽  
Preclinical Work

Abstract Cell adhesion-mediated resistance limits the success of cancer therapies and is a great obstacle to overcome in the clinic. Since the 1990s, where it became clear that adhesion of tumor cells to the extracellular matrix is an important mediator of therapy resistance, a lot of work has been conducted to understand the fundamental underlying mechanisms and two paradigms were deduced: cell adhesion-mediated radioresistance (CAM-RR) and cell adhesion-mediated drug resistance (CAM-DR). Preclinical work has evidently demonstrated that targeting of integrins, adapter proteins and associated kinases comprising the cell adhesion resistome is a promising strategy to sensitize cancer cells to both radiotherapy and chemotherapy. Moreover, the cell adhesion resistome fundamentally contributes to adaptation mechanisms induced by radiochemotherapy as well as molecular drugs to secure a balanced homeostasis of cancer cells for survival and growth. Intriguingly, this phenomenon provides a basis for synthetic lethal targeted therapies simultaneously administered to standard radiochemotherapy. In this review, we summarize current knowledge about the cell adhesion resistome and highlight targeting strategies to override CAM-RR and CAM-DR.

scholarly journals Ferroptosis Meets Cell–Cell Contacts

Cells ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 2462
Author(s):  
Cornelia Dietrich ◽  
Thomas G. Hofmann
Keyword(s):  
Cancer Cells ◽  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Cell Types ◽  
Therapy Resistance ◽  
Cell Contacts ◽  
Molecular Events ◽  
Underlying Mechanisms ◽  
Context Specific ◽  
Cell Cell

Ferroptosis is a regulated form of cell death characterized by iron dependency and increased lipid peroxidation. Initially assumed to be selectively induced in tumour cells, there is increasing evidence that ferroptosis plays an important role in pathophysiology and numerous cell types and tissues. Deregulated ferroptosis has been linked to human diseases, such as neurodegenerative diseases, cardiovascular disorders, and cancer. Along these lines, ferroptosis is a promising pathway to overcoming therapy resistance of cancer cells. It is therefore of utmost importance to understand the cellular signalling pathways and the molecular mechanisms underlying ferroptosis regulation, including context-specific effects mediated by the neighbouring cells through cell–cell contacts. Here, we give an overview on the molecular events and machinery linked to ferroptosis induction and commitment. We further summarize and discuss current knowledge about the role of cell–cell contacts, which differ in ferroptosis regulation between normal somatic cells and cancer cells. We present emerging concepts on the underlying mechanisms, address open questions, and discuss the possible impact of cell–cell contacts on exploiting ferroptosis in cancer therapy.

scholarly journals CXCL2-CXCR2 axis mediates αV integrin-dependent peritoneal metastasis of colon cancer cells

2021 ◽  
Author(s):  
Mattias Lepsenyi ◽  
Nader Algethami ◽  
Amr A. Al-Haidari ◽  
Anwar Algaber ◽  
Ingvar Syk ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Cell Adhesion ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Colon Cancer Cell ◽  
Colon Cancer Cells ◽  
Cancer Cell Adhesion ◽  
And Migration ◽  
Cxcr2 Antagonist

AbstractPeritoneal metastasis is an insidious aspect of colorectal cancer. The aim of the present study was to define mechanisms regulating colon cancer cell adhesion and spread to peritoneal wounds after abdominal surgery. Mice was laparotomized and injected intraperitoneally with CT-26 colon carcinoma cells and metastatic noduli in the peritoneal cavity was quantified after treatment with a CXCR2 antagonist or integrin-αV-antibody. CT-26 cells expressed cell surface chemokine receptors CXCR2, CXCR3, CXCR4 and CXCR5. Stimulation with the CXCR2 ligand, CXCL2, dose-dependently increased proliferation and migration of CT-26 cells in vitro. The CXCR2 antagonist, SB225002, dose-dependently decreased CXCL2-induced proliferation and migration of colon cancer cells in vitro. Intraperitoneal administration of CT-26 colon cancer cells resulted in wide-spread growth of metastatic nodules at the peritoneal surface of laparotomized animals. Laparotomy increased gene expression of CXCL2 at the incisional line. Pretreatment with CXCR2 antagonist reduced metastatic nodules by 70%. Moreover, stimulation with CXCL2 increased CT-26 cell adhesion to extracellular matrix (ECM) proteins in a CXCR2-dependent manner. CT-26 cells expressed the αV, β1 and β3 integrin subunits and immunoneutralization of αV abolished CXCL2-triggered adhesion of CT-26 to vitronectin, fibronectin and fibrinogen. Finally, inhibition of the αV integrin significantly attenuated the number of carcinomatosis nodules by 69% in laparotomized mice. These results were validated by use of the human colon cancer cell line HT-29 in vitro. Our data show that colon cancer cell adhesion and growth on peritoneal wound sites is mediated by a CXCL2-CXCR2 signaling axis and αV integrin-dependent adhesion to ECM proteins.

scholarly journals Therapeutic Perspectives of Molecules from Urtica dioica Extracts for Cancer Treatment

Molecules ◽  
2019 ◽  
Vol 24 (15) ◽  
pp. 2753 ◽  
Author(s):  
Sabrina Esposito ◽  
Alessandro Bianco ◽  
Rosita Russo ◽  
Antimo Di Maro ◽  
Carla Isernia ◽  
...  
Keyword(s):  
Natural Products ◽  
Cancer Cells ◽  
Current Knowledge ◽  
Biological Activities ◽  
Urtica Dioica ◽  
Cancer Therapies ◽  
Edible Plant ◽  
Bioactive Natural Products ◽  
Human Cancers ◽  
Anti Cancer

A large range of chronic and degenerative diseases can be prevented through the use of food products and food bioactives. This study reports the health benefits and biological activities of the Urtica dioica (U. dioica) edible plant, with particular focus on its cancer chemopreventive potential. Numerous studies have attempted to investigate the most efficient anti-cancer therapy with few side effects and high toxicity on cancer cells to overcome the chemoresistance of cancer cells and the adverse effects of current therapies. In this regard, natural products from edible plants have been assessed as sources of anti-cancer agents. In this article, we review current knowledge from studies that have examined the cytotoxic, anti-tumor and anti-metastatic effects of U. dioica plant on several human cancers. Special attention has been dedicated to the treatment of breast cancer, the most prevalent cancer among women and one of the main causes of death worldwide. The anti-proliferative and apoptotic effects of U. dioica have been demonstrated on different human cancers, investigating the properties of U. dioica at cellular and molecular levels. The potent cytotoxicity and anti-cancer activity of the U. dioica extracts are due to its bioactive natural products content, including polyphenols which reportedly possess anti-oxidant, anti-mutagenic and anti-proliferative properties. The efficacy of this edible plant to prevent or mitigate human cancers has been demonstrated in laboratory conditions as well as in experimental animal models, paving the way to the development of nutraceuticals for new anti-cancer therapies.

Calreticulin activates β1 integrin via fucosylation by fucosyltransferase 1 in J82 human bladder cancer cells

2014 ◽  
Vol 460 (1) ◽  
pp. 69-80 ◽  
Author(s):  
Yi-Chien Lu ◽  
Chiung-Nien Chen ◽  
Chia-Ying Chu ◽  
JenHer Lu ◽  
Bo-Jeng Wang ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Cell Adhesion ◽  
Cancer Cells ◽  
Cancer Patients ◽  
Β1 Integrin ◽  
Human Bladder Cancer ◽  
Human Bladder ◽  
Cancer Cell Adhesion ◽  
Bladder Cancer Cells ◽  
Human Bladder Cancer Cells

We demonstrated that calreticulin regulated bladder cancer cell adhesion through modifying α1,2-linked glycan on β1-integrin, which was catalysed by fucosyltransferase 1. Most importantly, higher levels of fucosylation directly activated β1-integrin. We provide a potential clinical treatment strategy for bladder cancer patients.

scholarly journals Integrin Trafficking and Tumor Progression

2012 ◽  
Vol 2012 ◽  
pp. 1-7 ◽  
Author(s):  
Sejeong Shin ◽  
Laura Wolgamott ◽  
Sang-Oh Yoon
Keyword(s):  
Extracellular Matrix ◽  
Cell Migration ◽  
Cell Adhesion ◽  
Tumor Progression ◽  
Cancer Cells ◽  
Anticancer Drugs ◽  
Cancer Cell ◽  
Molecular Mechanisms ◽  
Cancer Cell Adhesion

Integrins are major mediators of cancer cell adhesion to extracellular matrix. Through this interaction, integrins play critical roles in cell migration, invasion, metastasis, and resistance to apoptosis during tumor progression. Recent studies highlight the importance of integrin trafficking, endocytosis and recycling, for the functions of integrins in cancer cells. Understanding the molecular mechanisms of integrin trafficking is pivotal for understanding tumor progression and for the development of anticancer drugs.

scholarly journals Identifying collateral and synthetic lethal vulnerabilities within the DNA-damage response

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Pietro Pinoli ◽  
Sriganesh Srihari ◽  
Limsoon Wong ◽  
Stefano Ceri
Keyword(s):  
Cancer Cells ◽  
Synthetic Lethality ◽  
Mutual Exclusion ◽  
Copy Number Variations ◽  
Cancer Therapies ◽  
Synthetic Lethal ◽  
Gene Pairs ◽  
Synthetically Lethal ◽  
Highly Correlated ◽  
Exclusive Group

Abstract Background A pair of genes is defined as synthetically lethal if defects on both cause the death of the cell but a defect in only one of the two is compatible with cell viability. Ideally, if A and B are two synthetic lethal genes, inhibiting B should kill cancer cells with a defect on A, and should have no effects on normal cells. Thus, synthetic lethality can be exploited for highly selective cancer therapies, which need to exploit differences between normal and cancer cells. Results In this paper, we present a new method for predicting synthetic lethal (SL) gene pairs. As neighbouring genes in the genome have highly correlated profiles of copy number variations (CNAs), our method clusters proximal genes with a similar CNA profile, then predicts mutually exclusive group pairs, and finally identifies the SL gene pairs within each group pairs. For mutual-exclusion testing we use a graph-based method which takes into account the mutation frequencies of different subjects and genes. We use two different methods for selecting the pair of SL genes; the first is based on the gene essentiality measured in various conditions by means of the “Gene Activity Ranking Profile” GARP score; the second leverages the annotations of gene to biological pathways. Conclusions This method is unique among current SL prediction approaches, it reduces false-positive SL predictions compared to previous methods, and it allows establishing explicit collateral lethality relationship of gene pairs within mutually exclusive group pairs.

scholarly journals Targeting Glucose Metabolism to Overcome Resistance to Anticancer Chemotherapy in Breast Cancer

Cancers ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 2252 ◽  
Author(s):  
Elizabeth Varghese ◽  
Samson Mathews Samuel ◽  
Alena Líšková ◽  
Marek Samec ◽  
Peter Kubatka ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Glucose Metabolism ◽  
Cancer Cells ◽  
Current Knowledge ◽  
Expression Profiles ◽  
Morphological Characteristics ◽  
Therapy Resistance ◽  
Glycolytic Enzymes ◽  
Metabolic Inhibitors ◽  
Altered Glucose

Breast cancer (BC) is the most prevalent cancer in women. BC is heterogeneous, with distinct phenotypical and morphological characteristics. These are based on their gene expression profiles, which divide BC into different subtypes, among which the triple-negative breast cancer (TNBC) subtype is the most aggressive one. The growing interest in tumor metabolism emphasizes the role of altered glucose metabolism in driving cancer progression, response to cancer treatment, and its distinct role in therapy resistance. Alterations in glucose metabolism are characterized by increased uptake of glucose, hyperactivated glycolysis, decreased oxidative phosphorylation (OXPHOS) component, and the accumulation of lactate. These deviations are attributed to the upregulation of key glycolytic enzymes and transporters of the glucose metabolic pathway. Key glycolytic enzymes such as hexokinase, lactate dehydrogenase, and enolase are upregulated, thereby conferring resistance towards drugs such as cisplatin, paclitaxel, tamoxifen, and doxorubicin. Besides, drug efflux and detoxification are two energy-dependent mechanisms contributing to resistance. The emergence of resistance to chemotherapy can occur at an early or later stage of the treatment, thus limiting the success and outcome of the therapy. Therefore, understanding the aberrant glucose metabolism in tumors and its link in conferring therapy resistance is essential. Using combinatory treatment with metabolic inhibitors, for example, 2-deoxy-D-glucose (2-DG) and metformin, showed promising results in countering therapy resistance. Newer drug designs such as drugs conjugated to sugars or peptides that utilize the enhanced expression of tumor cell glucose transporters offer selective and efficient drug delivery to cancer cells with less toxicity to healthy cells. Last but not least, naturally occurring compounds of plants defined as phytochemicals manifest a promising approach for the eradication of cancer cells via suppression of essential enzymes or other compartments associated with glycolysis. Their benefits for human health open new opportunities in therapeutic intervention, either alone or in combination with chemotherapeutic drugs. Importantly, phytochemicals as efficacious instruments of anticancer therapy can suppress events leading to chemoresistance of cancer cells. Here, we review the current knowledge of altered glucose metabolism in contributing to resistance to classical anticancer drugs in BC treatment and various ways to target the aberrant metabolism that will serve as a promising strategy for chemosensitizing tumors and overcoming resistance in BC.

scholarly journals Using real-time impedance-based assays to monitor the effects of fibroblast-derived media on the adhesion, proliferation, migration and invasion of colon cancer cells

2014 ◽  
Vol 34 (4) ◽  
Author(s):  
Catríona M. Dowling ◽  
Carmen Herranz Ors ◽  
Patrick A. Kiely
Keyword(s):  
Colon Cancer ◽  
Cell Adhesion ◽  
Cancer Treatment ◽  
Cancer Cells ◽  
Real Time ◽  
Colon Cancer Cell ◽  
Migration And Invasion ◽  
Colon Cancer Cells ◽  
Cancer Cell Adhesion ◽  
Kinetics Of

Here, we use an RTCA platform to assess the kinetics of colon cancer cell adhesion, proliferation, migration and invasion in response to media derived from fibroblasts. This work highlights the importance of considering the stromal environment in cancer treatment.

scholarly journals The Influence of VE-Cadherin on Adhesion and Incorporation of Breast Cancer Cells into Vascular Endothelium

2021 ◽  
Vol 22 (11) ◽  
pp. 6049
Author(s):  
Thomas Brock ◽  
Elisabeth Boudriot ◽  
Anke Klawitter ◽  
Marianne Großer ◽  
Trang T. P. Nguyen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Endothelial Cells ◽  
Cell Adhesion ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Breast Cancer Cells ◽  
Molecular Mechanisms ◽  
Breast Cancer Cell Lines ◽  
Tumor Cell Adhesion ◽  
Cancer Cell Adhesion

During metastasis, cancer cells that originate from the primary tumor circulate in the bloodstream, extravasate, and form micrometastases at distant locations. Several lines of evidence suggest that specific interactions between cancer cells and endothelial cells, in particular tumor cell adhesion to the endothelium and transendothelial migration, play a crucial role in extravasation. Here we have studied the role of vascular endothelial (VE)-cadherin which is expressed aberrantly by breast cancer cells and might promote such interactions. By comparing different human breast cancer cell lines, we observed that the number of cancer cells that adhered to endothelium correlated with VE-cadherin expression levels. VE-cadherin silencing experiments confirmed that VE-cadherin enhances cancer cell adhesion to endothelial cells. However, in contrast, the number of cancer cells that incorporated into the endothelium was not dependent on VE‑cadherin. Thus, it appears that cancer cell adhesion and incorporation are distinct processes that are governed by different molecular mechanisms. When cancer cells incorporated into the endothelial monolayer, they formed VE-cadherin positive contacts with endothelial cells. On the other hand, we also observed tumor cells that had displaced endothelial cells, reflecting either different modes of incorporation, or a temporal sequence where cancer cells first form contact with endothelial cells and then displace them to facilitate transmigration. Taken together, these results show that VE-cadherin promotes the adhesion of breast cancer cells to the endothelium and is involved in the initial phase of incorporation, but not their transmigration. Thus, VE-cadherin might be of relevance for therapeutic strategies aiming at preventing the metastatic spread of breast cancer cells.

scholarly journals Epigenetic Deregulation of Apoptosis in Cancers

Cancers ◽  
2021 ◽  
Vol 13 (13) ◽  
pp. 3210
Author(s):  
Ezgi Ozyerli-Goknar ◽  
Tugba Bagci-Onder
Keyword(s):  
Cancer Cells ◽  
Apoptotic Cell ◽  
Therapy Response ◽  
Therapy Resistance ◽  
Genetic Alterations ◽  
Cancer Therapies ◽  
Epigenetic Changes ◽  
Bet Inhibitors ◽  
Apoptosis Regulation ◽  
Drug Interventions

Cancer cells possess the ability to evade apoptosis. Genetic alterations through mutations in key genes of the apoptotic signaling pathway represent a major adaptive mechanism of apoptosis evasion. In parallel, epigenetic changes via aberrant modifications of DNA and histones to regulate the expression of pro- and antiapoptotic signal mediators represent a major complementary mechanism in apoptosis regulation and therapy response. Most epigenetic changes are governed by the activity of chromatin modifying enzymes that add, remove, or recognize different marks on histones and DNA. Here, we discuss how apoptosis signaling components are deregulated at epigenetic levels, particularly focusing on the roles of chromatin-modifying enzymes in this process. We also review the advances in cancer therapies with epigenetic drugs such as DNMT, HMT, HDAC, and BET inhibitors, as well as their effects on apoptosis modulation in cancer cells. Rewiring the epigenome by drug interventions can provide therapeutic advantage for various cancers by reverting therapy resistance and leading cancer cells to undergo apoptotic cell death.

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