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      Reversing the Tumor Target: Establishment of a Tumor Trap

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          Despite the tremendous progress made in the field of cancer therapy in recent years, certain solid tumors still cannot be successfully treated. Alongside classical treatments in the form of chemotherapy and/or radiotherapy, targeted treatments such as immunotherapy that cause fewer side effects emerge as new options in the clinics. However, these alternative treatments may not be useful for treating all types of cancers, especially for killing infiltrative and circulating tumor cells (CTCs). Recent advances pursue the trapping of these cancer cells within a confined area to facilitate their removal for therapeutic and diagnostic purposes. A good understanding of the mechanisms behind tumor cell migration may drive the design of traps that mimic natural tumor niches and guide the movement of the cancer cells. To bring this trapping idea into reality, strong efforts are being made to create structured materials that imitate myelinated fibers, blood vessels, or pre-metastatic niches and incorporate chemical cues such as chemoattractants or adhesive proteins. In this review, the different strategies used (or could be used) to trap tumor cells are described, and relevant examples of their performance are analyzed.

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          Tensional homeostasis and the malignant phenotype.

          Tumors are stiffer than normal tissue, and tumors have altered integrins. Because integrins are mechanotransducers that regulate cell fate, we asked whether tissue stiffness could promote malignant behavior by modulating integrins. We found that tumors are rigid because they have a stiff stroma and elevated Rho-dependent cytoskeletal tension that drives focal adhesions, disrupts adherens junctions, perturbs tissue polarity, enhances growth, and hinders lumen formation. Matrix stiffness perturbs epithelial morphogenesis by clustering integrins to enhance ERK activation and increase ROCK-generated contractility and focal adhesions. Contractile, EGF-transformed epithelia with elevated ERK and Rho activity could be phenotypically reverted to tissues lacking focal adhesions if Rho-generated contractility or ERK activity was decreased. Thus, ERK and Rho constitute part of an integrated mechanoregulatory circuit linking matrix stiffness to cytoskeletal tension through integrins to regulate tissue phenotype.
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            Real-time imaging reveals the single steps of brain metastasis formation.

            Brain metastasis frequently occurs in individuals with cancer and is often fatal. We used multiphoton laser scanning microscopy to image the single steps of metastasis formation in real time. Thus, it was possible to track the fate of individual metastasizing cancer cells in vivo in relation to blood vessels deep in the mouse brain over minutes to months. The essential steps in this model were arrest at vascular branch points, early extravasation, persistent close contacts to microvessels and perivascular growth by vessel cooption (melanoma) or early angiogenesis (lung cancer). Inefficient steps differed between the tumor types. Long-term dormancy was only observed for single perivascular cancer cells, some of which moved continuously. Vascular endothelial growth factor-A (VEGF-A) inhibition induced long-term dormancy of lung cancer micrometastases by preventing angiogenic growth to macrometastases. The ability to image the establishment of brain metastases in vivo provides new insights into their evolution and response to therapies.
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              Paul Ehrlich's magic bullet concept: 100 years of progress.

              Exceptional advances in molecular biology and genetic research have expedited cancer drug development tremendously. The declared paradigm is the development of 'personalized and tailored drugs' that precisely target the specific molecular defects of a cancer patient. It is therefore appropriate to revisit the intellectual foundations of the development of such agents, as many have shown great clinical success. One hundred years ago, Paul Ehrlich, the founder of chemotherapy, received the Nobel Prize for Physiology or Medicine. His postulate of creating 'magic bullets' for use in the fight against human diseases inspired generations of scientists to devise powerful molecular cancer therapeutics.

                Author and article information

                Front Pharmacol
                Front Pharmacol
                Front. Pharmacol.
                Frontiers in Pharmacology
                Frontiers Media S.A.
                12 August 2019
                : 10
                1CRCINA, INSERM, Université de Nantes, Université d’Angers , Angers, France
                2Departamento de Farmacología, Farmacia y Tecnología Farmacéutica, R + D Pharma Group (GI-1645), Facultad de Farmacia, Universidade de Santiago de Compostela , Santiago de Compostela, Spain
                3Center for Education and Research on Macromolecules (CERM), Université de Liège , Liège, Belgium
                Author notes

                Edited by: David A. Gewirtz, Virginia Commonwealth University, United States

                Reviewed by: Olivier Feron, Catholic University of Louvain, Belgium; Gaelle Vandermeulen, Catholic University of Louvain, Belgium

                *Correspondence: Emmanuel Garcion, emmanuel.garcion@ 123456univ-angers.fr

                This article was submitted to Pharmacology of Anti-Cancer Drugs, a section of the journal Frontiers in Pharmacology

                †These authors have contributed equally to this work

                Copyright © 2019 Najberg, Haji Mansor, Boury, Alvarez-Lorenzo and Garcion

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                Page count
                Figures: 4, Tables: 1, Equations: 0, References: 124, Pages: 12, Words: 6553


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