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The Biomedical Potential of Fiber Organization in Cancer

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The Biomedical Potential of Fiber Organization in Cancer bioengineering Review Navigating the Collagen Jungle: The Biomedical Potential of Fiber Organization in Cancer Jonathan N. Ouellette 1,2, Cole R. Drifka 1,2, Kelli B. Pointer 2, Yuming Liu 2, Tyler J Lieberthal 1 , W John Kao 1,3, John S. Kuo 4, Agnes G. Loeffler 5 and Kevin W. Eliceiri 1,2,6,7,* 1 Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, WI 53706, USA; [email protected] (J.N.O.); [email protected] (C.R.D.); [email protected] (T.J.L.); [email protected] (W.J.K.) 2 Laboratory for Optical and Computational Instrumentation, Center for Quantitative Cell Imaging, University of Wisconsin-Madison, Madison, WI 53706, USA; [email protected] (K.B.P.); [email protected] (Y.L.) 3 Department of Industrial and Manufacturing Systems Engineering, Faculty of Engineering, University of Hong Kong, Pokfulam, Hong Kong 4 Department of Neurosurgery, Dell Medical School, The University of Texas at Austin, Austin, TX 78712, USA; [email protected] 5 Department of Pathology, MetroHealth Medical Center, Cleveland, OH 44109, USA; aloeffl[email protected] 6 Department of Medical Physics, University of Wisconsin-Madison, Madison, WI 53705, USA 7 Morgridge Institute for Research, Madison, WI 53715, USA * Correspondence: [email protected] Abstract: Recent research has highlighted the importance of key tumor microenvironment features, notably the collagen-rich extracellular matrix (ECM) in characterizing tumor invasion and progres- sion. This led to great interest from both basic researchers and clinicians, including pathologists, Citation: Ouellette, J.N.; Drifka, C.R.; to include collagen fiber evaluation as part of the investigation of cancer development and progres- Pointer, K.B.; Liu, Y.; Lieberthal, T.J; sion. Fibrillar collagen is the most abundant in the normal extracellular matrix, and was revealed to Kao, W.J.; Kuo, J.S.; Loeffler, A.G.; be upregulated in many cancers. Recent studies suggested an emerging theme across multiple cancer Eliceiri, K.W. Navigating the Collagen types in which specific collagen fiber organization patterns differ between benign and malignant Jungle: The Biomedical Potential of tissue and also appear to be associated with disease stage, prognosis, treatment response, and other Fiber Organization in Cancer. Bioengineering 2021, 8, 17. https:// clinical features. There is great potential for developing image-based collagen fiber biomarkers for doi.org/10.3390/bioengineering8020017 clinical applications, but its adoption in standard clinical practice is dependent on further transla- tional and clinical evaluations. Here, we offer a comprehensive review of the current literature of Academic Editor: Gunjan Agarwal fibrillar collagen structure and organization as a candidate cancer biomarker, and new perspectives Received: 19 November 2020 on the challenges and next steps for researchers and clinicians seeking to exploit this information in Accepted: 13 January 2021 biomedical research and clinical workflows. Published: 21 January 2021 Keywords: fibrillar collagen; cancer; prognosis; tumor microenvironment; extracellular matrix; Publisher’s Note: MDPI stays neutral ECM; pathology with regard to jurisdictional claims in published maps and institutional affil- iations. 1. Introduction The tumor microenvironment consists of multiple biochemical, mechanical, and struc- tural signals. One of the major structural components of the tumor microenvironment Copyright: © 2021 by the authors. is the extracellular matrix (ECM). The ECM is a very dynamic structure consisting of Licensee MDPI, Basel, Switzerland. many components including collagen, laminin, fibronectin, glycoproteins, proteoglycans, This article is an open access article and polysaccharides (Figure1). There have been increasing efforts to better understand distributed under the terms and the influences of the ECM components on cell behaviors and functions. A major focus of conditions of the Creative Commons studying the ECM is the role of collagen in both normal and abnormal function. Collagen Attribution (CC BY) license (https:// is the most abundant ECM protein in the human body. There are twenty-eight different creativecommons.org/licenses/by/ 4.0/). types of collagen involved in many normal biological functions such as tissue scaffolding, Bioengineering 2021, 8, 17. https://doi.org/10.3390/bioengineering8020017 https://www.mdpi.com/journal/bioengineering Bioengineering 2021, 8, 17 2 of 19 Bioengineering 2021, 8, x FOR PEER REVIEW 2 of 18 scaffolding,cell adhesion, cell cell adhesion, migration, cell angiogenesis,migration, angiogenesis, tissue morphogenesis, tissue morphogenesis, and tissue and repair tissue [1]. repairBased [1]. on functionBased on andfunction domain and homologydomain ho [mology2], these [2], collagens these collagens are classified are classified into seven into sevengroups: groups: fibril-forming fibril-forming (fibrillar) (fibrillar) collagens, collag fibril-associatedens, fibril-associated collagens collagens with interruptedwith inter- ruptedtriple helices, triple network-forminghelices, network-forming collagens, collag transmembraneens, transmembrane collagens, collagens, endostatin-producing endostatin- producingcollagens, anchoringcollagens, fibrils,anchoring and fibrils, bead-filament-forming and bead-filament-forming collagens. collagens. Figure 1. Key extracellular matrix (ECM) components of the tumortumor microenvironment.microenvironment. Collagens Collagens,, laminin, fibronectin, fibronectin, proteoglycans, and other components are produced by fibroblasts and other resident cells. proteoglycans, and other components are produced by fibroblasts and other resident cells. Fibril-forming collagens, collagens, in in particular, particular, ar aree highly abundant throughout throughout the the stroma. stroma. Normally, fibrillarfibrillar collagens maintain tissue integrity and are separated from epithelialepithelial cells by a thin basement membrane (Figure1 1)).. ThereThere areare eleveneleven fibrillarfibrillar collagencollagen genesgenes that break break down down into into seven seven different different collagen collagen types: types: type type I, I, II, II, III, III, V, V, XI, XI, XXIV, XXIV, and and XXVII. XXVII. Molecular assembly of fibrillar fibrillar collagen is hierarchical [[3].3]. All collagen molecules consist of three polypeptide alpha chains (~1.6 nm width, ~300 nm length) that make at least one triple helical helical domain. domain. The The combination combination of of three three alpha alpha chains chains determines determines the the collagen collagen type. type. These alpha chains consist of around 1,000 amino acid residues with a characteristic triplet repeat sequence Gly-X-Y, alpha chain types are differentiated by the amino acid residues inin the X and Y positions of those triplets [4]. [4]. The The most abundant fibrillar fibrillar collagen, collagen, type type I, I, isis generally generally heterotrimeric heterotrimeric and and composed composed of of two two αα1(I)1(I) and and one one α2(I)α2(I) chains; chains; however, however, a homotrimerica homotrimeric αα1(I)1(I) isoform isoform has has been been found found to to be be pr producedoduced by by certain certain malignant malignant cells and isis resistant resistant to to proteolysis proteolysis [5]. [5]. Collagen Collagen types types II, II, III, III, XXIV, XXIV, and and XXVII XXVII are are composed composed of of ho- ho- motrimers. Collagen types V V and and XI XI are are often often found found as as heterotrimeric heterotrimeric molecules; molecules; however, however, homotrimers of the α1(V) chain have been characterized and composite molecules of type V and XI collagens have also been described. α3(XI) chains also appear to be a modifiedmodified product of of the the gene gene that that encodes encodes the the type type II IIcollagen collagen chain chain [2]. [2 Procollagen]. Procollagen containing containing N- andN- and C- propeptides C-propeptides at each at each end end of the of thetriple triple helical helical domains domains are ultimately are ultimately processed processed into collageninto collagen upon upon protease protease cleavage cleavage [6]. Collagen [6]. Collagen molecules molecules associate associate both bothin lateral in lateral and lon- and gitudinallongitudinal directions directions to form to form collagen collagen fibrils fibrils (~100 (~100 nm width, nm width, ~1 µm ~1 length)µm length) that are that stabi- are lizedstabilized by non-reducible by non-reducible covalent covalent cross-links cross-links that involve that involve residues residues in the intriple the triplehelix. helix.Mul- tipleMultiple fibrils fibrils can then can then aggregate aggregate to form to form collagen collagen fibers fibers (~1 µm (~1 width,µm width, ~10 µm ~10 length).µm length). Collagen fiber fiber formation formation is is essential essential to to human human health. health. Abnormalities Abnormalities in collagen in collagen ex- pressionexpression or orcollagen collagen structure structure can can result result in in debilitating debilitating disease. disease. Os Osteogenesisteogenesis imperfecta, imperfecta, for example,example, isis a a connective connective tissue tissue disorder disorder characterized characterized by bone by bone deformities, deformities, brittle bones,brittle bones,and low and bone low density bone density caused bycaused the improper by the im encodingproper encoding and assembly and assembly of collagen of typecollagen I [7]. typeOver Ithe [7]. last Over decade, the last there decade, has
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