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Oriented Collagen Fibers Direct Tumor Cell Intravasation Oriented collagen fibers direct tumor cell intravasation Weijing Hana, Shaohua Chenb, Wei Yuanc, Qihui Fana, Jianxiang Tianb, Xiaochen Wanga, Longqing Chend, Xixiang Zhange, Weili Weie, Ruchuan Liuf, Junle Quc, Yang Jiaob, Robert H. Austing,c,1, and Liyu Liuf,a,1 aKey Laboratory of Soft Matter Physics, Institute of Physics, Chinese Academy of Sciences, Beijing, China 100190; bMaterials Science and Engineering, Arizona State University, Tempe, AZ 85281; cKey Laboratory of Optoelectronic Devices and Systems of Ministry of Education and Guangdong Province, Shenzhen University, Shenzhen, China 518060; dDivision of Physical Science and Engineering, King Abdullah University of Science & Technology, Thuwal, Saudi Arabia 23955-6900; eInnovative Drug Research Center, Chongqing University, Chongqing, China 401331; fCollege of Physics, Chongqing University, Chongqing, China 401331; and gDepartment of Physics, Princeton University, Princeton, NJ 08544 Contributed by Robert H. Austin, July 28, 2016 (sent for review November 17, 2015; reviewed by Pascal Silberzan, Denis Wirtz, and Clare C. Yu) In this work, we constructed a Collagen I–Matrigel composite extra- surrounding the tumor lesion are parallel to the tumor boundary, cellular matrix (ECM). The composite ECM was used to determine where the collagen is located but without obviously specific the influence of the local collagen fiber orientation on the collective alignment (termed TACS-1) (12). Fig. 1 B, 1–3 represents in- intravasation ability of tumor cells. We found that the local fiber vasive ductal carcinoma at grade III. In this case, after cell de- alignment enhanced cell–ECM interactions. Specifically, metastatic velopment, collagen fiber (blue) and tumor cells (gray) have MDA-MB-231 breast cancer cells followed the local fiber alignment more mixed forms. Clearly, the filament-like collagen fibers show direction during the intravasation into rigid Matrigel (∼10 mg/mL macro alignment along the cell invasive directions (termed protein concentration). TACS-3) (12), which is believed to correlate with cell invasive potential in human tissues. cancer | intravasation | collagen | oriented invasion | microenvironment Recently, a number of mouse models and in vitro 3D cell culture systems have been used to study the cell underlying molecular and etastasis is a lethal milestone in cancer: Cells escape from mechanical mechanisms for local collagen fiber reorganization and Mthe confinement of primary tumor sites (intravasation), alignment. These experiments showed that epithelial cells and fi- invade tissues as well as the lymphatic and vascular systems, broblasts are capable of using associated proteins to initiate the and finally colonize (extravasation) distant sites. It has been Rho- and Rho kinase (Rock) pathway and then mediate actin- estimated that less than 1% of tumor cells undergo this pro- myosin contractility to orient collagen fibers (13, 16–18). However, cess, but metastasis contributes to more than 90% of cancer- it remains difficult to analyze the influences of the reorganized related deaths (1, 2). Metastasis involves both genetic and collagen tissue on tumor cells so far. The reason for that is mainly epigenetic alternation of tumor cells, as well as external bio- because precise quantification of reorganized collagen tissue chemical and biophysical microenvironments (3–5). Pathology in vivo is significantly restricted by existing methods. Therefore, studies suggest that metastatic tumor cells exhibit highly in vitro 3D models have been constructed to build linear oriented branched morphologies and distinct aligned registration with matrices in microchannels by mechanical strain and have demon- aligned extracellular matrix (ECM) during metastatic tumor strated that 3D matrix alignment facilitates persistent migration of progression (4, 5). tumor cells (9, 19–22). For example, Jimenez Valencia et al. We address three important questions concerning metastasis. studied cell behaviors in and around spheroids, which could be (i) Can we build in vitro complex ECM structures with hetero- regarded as a tumor model at an early stage of the intravasation geneously oriented collagen fibers and basement membrane process. The analysis showed that the cells aligned perpendicularly components to mimic the cancer cell intravasation process? to the spheroid surface due to applied traction forces from the cells (ii) How does aligned collagen influence cell intravasation into/ in the spheroid to reorganize the collagen matrix (23). Although through the basement membrane before entering vessels? the density and alignment of fibrillary collagen are clearly impor- (iii) After cell detachment from the primary tumor site, how does a tant markers in diagnosing a human breast carcinoma’sstage(12, heterogeneous ECM with a varying degree of local fiber alignment 14), biopsies merely provide static “snapshots” of the morphology influence cell intravasation and subsequent penetration into the basement membrane during their intravasation process? The major Significance obstacle to addressing these questions is the difficulty in constructing both an in vitro 3D microenvironment to mimic the above process Intravasation is an early stage of metastasis that involves met- and flexible controls of the environmental parameters, such as fiber astatic cells moving from the tumor into the extracellular matrix orientations in a complex collagen/Matrigel composite, nutrition, (ECM), breakthrough of the basement membrane, and entry into oxygen, drug concentrations, etc. blood vessels. We found that the oriented fibers greatly enhance In breast cancer metastasis, cancer cells are believed to reor- and facilitate the metastatic cell intravasation process during ganize and progress through the interstitial ECM matrix, break metastasis. We suggest that a possible “tissue treatment” ther- through the basement membrane, and enter blood vessels or apy could be considered, in which the ECM fiber structure ori- lymphatic capillaries (6–10). Fig. 1C presents a schematic illustra- entation in the tumor microenvironment might be altered to tion of the intravasation process in metastasis. Tumor-associated minimize the intravasation rate of metastatic cells. collagen signatures (TACS), basically environmentally elevated collagen density and collagen fiber reorganization, are used to Author contributions: W.H., S.C., W.Y., Q.F., X.W., L.C., X.Z., J.Q., Y.J., and L.L. designed stage mammary carcinoma tumor progression levels (6, 11–13). research; W.H., S.C., W.Y., Q.F., J.T., X.W., L.C., X.Z., and L.L. performed research; W.H., S.C., W.Y., Q.F., J.T., X.W., L.C., X.Z., J.Q., Y.J., R.H.A., and L.L. analyzed data; and W.W., Fig. 1 presents hematoxylin/eosin (H&E)-stained biopsy slices of R.L., Y.J., R.H.A., and L.L. wrote the paper. breast cancer imaged by second harmonic generation (SHG) under Reviewers: P.S., Institut Curie-Centre de Recherche; D.W., The Johns Hopkins University; a two-photon confocal microscopy (A1R MP; Nikon) (detailed and C.C.Y., University of California, Irvine. information provided in SI Appendix, SI Text) (6, 14, 15). Fig. 1 A, The authors declare no conflict of interest. – 1 3 shows the stained human invasive ductal carcinoma tumor 1To whom correspondence may be addressed. Email: [email protected] or austin@ at grade I. In the enlarged figures (Fig. 1 A, 2 and 3), the cells princeton.edu. have well-defined borders between the epithelium (gray) and This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. stromal collagen (blue). The collagen fibers with higher density 1073/pnas.1610347113/-/DCSupplemental. 11208–11213 | PNAS | October 4, 2016 | vol. 113 | no. 40 www.pnas.org/cgi/doi/10.1073/pnas.1610347113 Downloaded by guest on September 25, 2021 Fig. 1. Clinic biopsy of breast carcinoma progression at early (TACS-1) and late (TACS-3) stages. (A, 1–3) show the H&E-stained slices of tumor cell devel- opment during the TACS-1 stage. (A, 2) A second harmonic generation (SHG) image illustrating the complexity and variability of collagen localization. Combined with bright-field cell images, it seems that the locally dense collagen matrix surrounds ducts with a spherical morphology. For TACS-3 (B, 1–3), the tumor cells (gray color in B, 3) seem to interact with the parallel aligned collagen fibers for their invasion. (C) Drawing illustrating that metastatic tumor cells interact with oriented ECM fibers and invade toward the basement membrane and vessels during the intravasation process. The color depth represents the nutrient gradient in the tissues; higher nutrition in vessels is an attraction for cell intravasation into tissues. of cells and collagen fibers. Further, although there have been pillar-like inner structures would efficiently stabilize gel structures inside and constructs of homogeneous localized collagen alignments and avoid unflavored mechanical influence by the fluid at the side channels (24). of systematic quantified fiber alignment and associated cell dis- Matrigel (100% concentration, 356237; Corning) and Collagen I (2 mg/mL placement (9), a basic in vitro 3D ECM model for intravasation in water, 354236; Corning) created the sandwiched ECM. The heterogeneous study should at least include structures mimicking both the in- Collagen I orientation was induced by internally developing strain fields due terstitial matrix (collagen) and basement membrane (Matrigel), to the Matrigel volume swelling upon setting (25–29). Fig. 2B shows the with various degrees of
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