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      Computational and Experimental Models of Cancer Cell Response to Fluid Shear Stress

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          Abstract

          It has become evident that mechanical forces play a key role in cancer metastasis, a complex series of steps that is responsible for the majority of cancer-related deaths. One such force is fluid shear stress, exerted on circulating tumor cells by blood flow in the vascular microenvironment, and also on tumor cells exposed to slow interstitial flows in the tumor microenvironment. Computational and experimental models have the potential to elucidate metastatic behavior of cells exposed to such forces. Here, we review the fluid-generated forces that tumor cells are exposed to in the vascular and tumor microenvironments, and discuss recent computational and experimental models that have revealed mechanotransduction phenomena that may play a role in the metastatic process.

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          Balancing forces: architectural control of mechanotransduction.

          All cells exist within the context of a three-dimensional microenvironment in which they are exposed to mechanical and physical cues. These cues can be disrupted through perturbations to mechanotransduction, from the nanoscale-level to the tissue-level, which compromises tensional homeostasis to promote pathologies such as cardiovascular disease and cancer. The mechanisms of such perturbations suggest that a complex interplay exists between the extracellular microenvironment and cellular function. Furthermore, sustained disruptions in tensional homeostasis can be caused by alterations in the extracellular matrix, allowing it to serve as a mechanically based memory-storage device that can perpetuate a disease or restore normal tissue behaviour.
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            Role of extracellular matrix assembly in interstitial transport in solid tumors.

            The extracellular matrix (ECM) may contribute to the drug resistance of a solid tumor by preventing the penetration of therapeutic agents. We measured differences in interstitial resistance to macromolecule (IgG) motion in four tumor types and found an unexpected correspondence between transport resistance and the mechanical stiffness. The interstitial diffusion coefficient of IgG was measured in situ by fluorescence redistribution after photobleaching. Tissue elastic modulus and hydraulic conductivity were measured by confined compression of excised tissue. In apparent contradiction to an existing paradigm, these functional properties are correlated with total tissue content of collagen, not glycosaminoglycan. An extended collagen network was observed in the more penetration-resistant tumors. Collagenase treatment of the more penetration-resistant tumors significantly increased the IgG interstitial diffusion rate. We conclude that collagen influences the tissue resistance to macromolecule transport, possibly by binding and stabilizing the glycosaminoglycan component of the ECM. These findings suggest a new method to screen tumors for potential resistance to macromolecule-based therapy. Moreover, collagen and collagen-proteoglycan bonds are identified as potential targets of treatment to improve macromolecule delivery.
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              Stromal fibroblasts in cancer: a novel tumor-promoting cell type.

              Tumors are highly complex tissues composed of neoplastic cells and, in the case of carcinomas, stromal cell compartments containing a variety of mesenchymal cells, notably fibroblasts, myofibroblasts, endothelial cells, pericytes, and a variety of inflammatory cells associated with the immune system. Fibroblasts and myofibroblasts often represent the majority of the stromal cells within various types of human carcinomas, yet the specific contributions of these cells to tumor growth are poorly understood. Recent work has demonstrated that stromal fibroblast fractions, named carcinoma-associated fibroblasts (CAFs), that have been extracted from a number of invasive human breast carcinomas are more competent to promote the growth of mammary carcinoma cells and to enhance tumor angiogenesis than are comparable cells derived from outside of these tumor masses. CAFs include large populations of myofibroblasts that secrete elevated levels of stromal cell-derived factor 1 (SDF-1), also called CXCL12, which plays a central role in the promotion of tumor growth and angiogenesis; CAF-derived SDF-1 not only stimulates carcinoma cell growth directly through the CXCR4 receptor displayed on tumor cells but also serves to recruit endothelial progenitor cells (EPCs) into tumors, thereby furthering neoangiogenesis. In this review, we highlight the importance of this SDF-1-CXCR4 signaling pathway in the tumor microenvironment and discuss the mechanisms by which stromal fibroblasts within mammary carcinomas enhance tumor growth.
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                Author and article information

                Journal
                Front Oncol
                Front Oncol
                Front. Oncol.
                Frontiers in Oncology
                Frontiers Media S.A.
                2234-943X
                07 February 2013
                05 March 2013
                2013
                : 3
                : 44
                Affiliations
                [1] 1Department of Biomedical Engineering, Cornell University Ithaca, NY, USA
                Author notes

                Edited by: Katarzyna A. Rejniak, H. Lee Moffitt Cancer Center & Research Institute, USA

                Reviewed by: Christian Stock, University of Muenster, Germany; Owen McCarty, Oregon Health and Science University, USA

                *Correspondence: Michael R. King, Department of Biomedical Engineering, Cornell University, 205 Weill Hall, Ithaca, NY 14853, USA. e-mail: mike.king@ 123456cornell.edu

                This article was submitted to Frontiers in Molecular and Cellular Oncology, a specialty of Frontiers in Oncology.

                Article
                10.3389/fonc.2013.00044
                3587800
                23467856
                da60c75d-fef2-4ebc-ad81-84a328104de9
                Copyright © 2013 Mitchell and King.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in other forums, provided the original authors and source are credited and subject to any copyright notices concerning any third-party graphics etc.

                History
                : 15 January 2013
                : 18 February 2013
                Page count
                Figures: 5, Tables: 0, Equations: 6, References: 121, Pages: 11, Words: 9719
                Categories
                Oncology
                Review Article

                Oncology & Radiotherapy
                cancer metastasis,circulating tumor cells,mechanotransduction,shear stress,blood,interstitial flow

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