Abstract

During the migration of cancer cells for metastasis, cancer cells can be exposed to fluid shear conditions. We examined two breast cancer cell lines, MDA-MB-468 (less metastatic) and MDA-MB-231 (more metastatic), and a benign MCF-10A epithelial cell line for their responsiveness in migration to fluid shear. We tested fluid shear at 15 dyne/cm2 that can be encountered during breast cancer cells traveling through blood vessels or metastasizing to mechanically active tissues such as bone. MCF-10A exhibited the least migration with a trend of migrating in the flow direction. Intriguingly, fluid shear played a potent role as a trigger for MDA-MB-231 cell migration, inducing directional migration along the flow with significantly increased displacement length and migration speed and decreased arrest coefficient relative to unflowed MDA-MB-231. In contrast, MDA-MB-468 cells were markedly less migratory than MDA-MB-231 cells, and responded very poorly to fluid shear. As a result, MDA-MB-468 cells did not exhibit noticeable difference in migration between static and flow conditions, as was distinct in root-mean-square (RMS) displacement—an ensemble average of all participating cells. These may suggest that the difference between more metastatic MDA-MB-231 and less metastatic MDA-MB-468 breast cancer cells could be at least partly involved with their differential responsiveness to fluid shear stimulatory cues. Our study provides new data in regard to potential crosstalk between fluid shear and metastatic potential in mediating breast cancer cell migration.

References

References
1.
Leber
,
M. F.
, and
Efferth
,
T.
,
2009
, “
Molecular Principles of Cancer Invasion and Metastasis (Review)
,”
Int. J. Oncol.
,
34
(
4
), pp.
881
895
.10.3892/ijo_00000214
2.
Mareel
,
M.
, and
Leroy
,
A.
,
2003
, “
Clinical, Cellular, and Molecular Aspects of Cancer Invasion
,”
Physiol. Rev.
,
83
(
2
), pp.
337
376
.10.1152/physrev.00024.2002
3.
Arrigoni
,
C.
,
Bersini
,
S.
,
Gilardi
,
M.
, and
Moretti
,
M.
,
2016
, “
In Vitro Co-Culture Models of Breast Cancer Metastatic Progression Towards Bone
,”
Int. J. Mol. Sci.
,
17
(
9
), p.
1405
.10.3390/ijms17091405
4.
Butcher
,
D. T.
,
Alliston
,
T.
, and
Weaver
,
V. M.
,
2009
, “
A Tense Situation: Forcing Tumour Progression
,”
Nat. Rev. Cancer
,
9
(
2
), pp.
108
122
.10.1038/nrc2544
5.
Swartz
,
M. A.
, and
Lund
,
A. W.
,
2012
, “
Lymphatic and Interstitial Flow in the Tumour Microenvironment: Linking Mechanobiology With Immunity
,”
Nat. Rev. Cancer
,
12
(
3
), pp.
210
219
.10.1038/nrc3186
6.
Huang
,
Y. L.
,
Tung
,
C. K.
,
Zheng
,
A.
,
Kim
,
B. J.
, and
Wu
,
M.
,
2015
, “
Interstitial Flows Promote Amoeboid Over Mesenchymal Motility of Breast Cancer Cells Revealed by a Three Dimensional Microfluidic Model
,”
Integr. Biol. (Camb.)
,
7
(
11
), pp.
1402
1411
.10.1039/C5IB00115C
7.
Wiig
,
H.
, and
Swartz
,
M. A.
,
2012
, “
Interstitial Fluid and Lymph Formation and Transport: Physiological Regulation and Roles in Inflammation and Cancer
,”
Physiol. Rev.
,
92
(
3
), pp.
1005
1060
.10.1152/physrev.00037.2011
8.
Malek
,
A. M.
,
Alper
,
S. L.
, and
Izumo
,
S.
,
1999
, “
Hemodynamic Shear Stress and Its Role in Atherosclerosis
,”
JAMA
,
282
(
21
), pp.
2035
2042
.10.1001/jama.282.21.2035
9.
Orr
,
D. E.
, and
Burg
,
K. J. L.
,
2008
, “
Design of a Modular Bioreactor to Incorporate Both Perfusion Flow and Hydrostatic Compression for Tissue Engineering Applications
,”
Ann. Biomed. Eng.
,
36
(
7
), pp.
1228
1241
.10.1007/s10439-008-9505-0
10.
Debnath
,
J.
,
Muthuswamy
,
S. K.
, and
Brugge
,
J. S.
,
2003
, “
Morphogenesis and Oncogenesis of MCF-10A Mammary Epithelial Acini Grown in Three-Dimensional Basement Membrane Cultures
,”
Methods
,
30
(
3
), pp.
256
268
.10.1016/S1046-2023(03)00032-X
11.
Neve
,
R. M.
,
Chin
,
K.
,
Fridlyand
,
J.
,
Yeh
,
J.
,
Baehner
,
F. L.
,
Fevr
,
T.
,
Clark
,
L.
,
Bayani
,
N.
,
Coppe
,
J. P.
,
Tong
,
F.
,
Speed
,
T.
,
Spellman
,
P. T.
,
DeVries
,
S.
,
Lapuk
,
A.
,
Wang
,
N. J.
,
Kuo
,
W. L.
,
Stilwell
,
J. L.
,
Pinkel
,
D.
,
Albertson
,
D. G.
,
Waldman
,
F. M.
,
McCormick
,
F.
,
Dickson
,
R. B.
,
Johnson
,
M. D.
,
Lippman
,
M.
,
Ethier
,
S.
,
Gazdar
,
A.
, and
Gray
,
J. W.
,
2006
, “
A Collection of Breast Cancer Cell Lines for the Study of Functionally Distinct Cancer Subtypes
,”
Cancer Cell
,
10
(
6
), pp.
515
527
.10.1016/j.ccr.2006.10.008
12.
Cailleau
,
R.
,
Olivé
,
M.
, and
Cruciger
,
Q. V.
,
1978
, “
Long-Term Human Breast Carcinoma Cell Lines of Metastatic Origin: Preliminary Characterization
,”
Vitro
,
14
(
11
), pp.
911
915
.10.1007/BF02616120
13.
Holliday
,
D. L.
, and
Speirs
,
V.
,
2011
, “
Choosing the Right Cell Line for Breast Cancer Research
,”
Breast Cancer Res.
,
13
(
4
), p.
215
.10.1186/bcr2889
14.
Riehl
,
B. D.
,
Lee
,
J. S.
,
Ha
,
L.
, and
Lim
,
J. Y.
,
2015
, “
Fluid-Flow-Induced Mesenchymal Stem Cell Migration: Role of Focal Adhesion Kinase and RhoA Kinase Sensors
,”
J. R. Soc. Interface
,
12
(
104
), p.
20141351
.10.1098/rsif.2014.1351
15.
Riehl
,
B. D.
,
Lee
,
J. S.
,
Ha
,
L.
,
Kwon
,
I. K.
, and
Lim
,
J. Y.
,
2017
, “
Flowtaxis of Osteoblast Migration Under Fluid Shear and the Effect of RhoA Kinase Silencing
,”
PLoS One
,
12
(
2
), p.
e0171857
.10.1371/journal.pone.0171857
16.
Riddle
,
R. C.
,
Hippe
,
K. R.
, and
Donahue
,
H. J.
,
2008
, “
Chemotransport Contributes to the Effect of Oscillatory Fluid Flow on Human Bone Marrow Stromal Cell Proliferation
,”
J. Orthop. Res.
,
26
(
7
), pp.
918
924
.10.1002/jor.20637
17.
Salvi
,
J. D.
,
Lim
,
J. Y.
, and
Donahue
,
H. J.
,
2010
, “
Increased Mechanosensitivity of Cells Cultured on Nanotopographies
,”
J. Biomech.
,
43
(
15
), pp.
3058
3062
.10.1016/j.jbiomech.2010.07.015
18.
Salvi
,
J. D.
,
Lim
,
J. Y.
, and
Donahue
,
H. J.
,
2010
, “
Finite Element Analyses of Fluid Flow Conditions in Cell Culture
,”
Tissue Eng. Part C Methods
,
16
(
4
), pp.
661
670
.10.1089/ten.tec.2009.0159
19.
Schindelin
,
J.
,
Arganda-Carreras
,
I.
,
Frise
,
E.
,
Kaynig
,
V.
,
Longair
,
M.
,
Pietzsch
,
T.
,
Preibisch
,
S.
,
Rueden
,
C.
,
Saalfeld
,
S.
,
Schmid
,
B.
,
Tinevez
,
J. Y.
,
White
,
D. J.
,
Hartenstein
,
V.
,
Eliceiri
,
K.
,
Tomancak
,
P.
, and
Cardona
,
A.
,
2012
, “
Fiji: An Open-Source Platform for Biological-Image Analysis
,”
Nat. Methods
,
9
(
7
), pp.
676
682
.10.1038/nmeth.2019
20.
Huth
,
J.
,
Buchholz
,
M.
,
Kraus
,
J. M.
,
Schmucker
,
M.
,
von Wichert
,
G.
,
Krndija
,
D.
,
Seufferlein
,
T.
,
Gress
,
T. M.
, and
Kestler
,
H. A.
,
2010
, “
Significantly Improved Precision of Cell Migration Analysis in Time-Lapse Video Microscopy Through Use of a Fully Automated Tracking System
,”
BMC Cell Biol.
,
11
(
1
), p.
24
.10.1186/1471-2121-11-24
21.
Shields
,
J. D.
,
Fleury
,
M. E.
,
Yong
,
C.
,
Tomei
,
A. A.
,
Randolph
,
G. J.
, and
Swartz
,
M. A.
,
2007
, “
Autologous Chemotaxis as a Mechanism of Tumor Cell Homing to Lymphatics Via Interstitial Flow and Autocrine CCR7 Signaling
,”
Cancer Cell
,
11
(
6
), pp.
526
538
.10.1016/j.ccr.2007.04.020
22.
Polacheck
,
W. J.
,
Charest
,
J. L.
, and
Kamm
,
R. D.
,
2011
, “
Interstitial Flow Influences Direction of Tumor Cell Migration Through Competing Mechanisms
,”
Proc. Natl. Acad. Sci. U.S.A.
,
108
(
27
), pp.
11115
11120
.10.1073/pnas.1103581108
23.
Andalib
,
M. N.
,
Dzenis
,
Y.
,
Donahue
,
H. J.
, and
Lim
,
J. Y.
,
2016
, “
Biomimetic Substrate Control of Cellular Mechanotransduction
,”
Biomater. Res.
,
20
, p.
11
.10.1186/s40824-016-0059-1
24.
Haessler
,
U.
,
Teo
,
J. C.
,
Foretay
,
D.
,
Renaud
,
P.
, and
Swartz
,
M. A.
,
2012
, “
Migration Dynamics of Breast Cancer Cells in a Tunable 3D Interstitial Flow Chamber
,”
Integr. Biol.
,
4
(
4
), pp.
401
409
.10.1039/c1ib00128k
25.
Tarbell
,
J. M.
, and
Cancel
,
L. M.
,
2016
, “
The Glycocalyx and Its Significance in Human Medicine
,”
J. Intern. Med.
,
280
(
1
), pp.
97
113
.10.1111/joim.12465
26.
Qazi
,
H.
,
Palomino
,
R.
,
Shi
,
Z. D.
,
Munn
,
L. L.
, and
Tarbell
,
J. M.
,
2013
, “
Cancer Cell Glycocalyx Mediates Mechanostransduction and Flow-Regulated Invasion
,”
Integr. Biol.
,
5
(
11
), pp.
1334
1343
.10.1039/c3ib40057c
27.
Demou
,
Z. N.
,
2010
, “
Gene Expression Profiles in 3D Tumor Analogs Indicate Compressive Strain Differentially Enhances Metastatic Potential
,”
Ann. Biomed. Eng.
,
38
(
11
), pp.
3509
3520
.10.1007/s10439-010-0097-0
28.
Cross
,
S. E.
,
Jin
,
Y. S.
,
Rao
,
J.
, and
Gimzewski
,
J. K.
,
2007
, “
Nanomechanical Analysis of Cells From Cancer Patients
,”
Nat. Nanotechnol.
,
2
(
12
), pp.
780
783
.10.1038/nnano.2007.388
29.
Suresh
,
S.
,
2007
, “
Biomechanics and Biophysics of Cancer Cells
,”
Acta Biomater.
,
3
(
4
), pp.
413
438
.10.1016/j.actbio.2007.04.002
30.
Taherian
,
A.
,
Li
,
X.
,
Liu
,
Y.
, and
Haas
,
T. A.
,
2011
, “
Differences in Integrin Expression and Signaling Within Human Breast Cancer Cells
,”
BMC Cancer
,
11
(
1
), p.
293
.10.1186/1471-2407-11-293
31.
Singh
,
C.
,
Shyanti
,
R. K.
,
Singh
,
V.
,
Kale
,
R. K.
,
Mishra
,
J. P. N.
, and
Singh
,
R. P.
,
2018
, “
Integrin Expression and Glycosylation Patterns Regulate Cell-Matrix Adhesion and Alter With Breast Cancer Progression
,”
Biochem. Biophys. Res. Commun.
,
499
(
2
), pp.
374
380
.10.1016/j.bbrc.2018.03.169
32.
Veß
,
A.
,
Blache
,
U.
,
Leitner
,
L.
,
Kurz
,
A. R. M.
,
Ehrenpfordt
,
A.
,
Sixt
,
M.
, and
Posern
,
G.
,
2017
, “
A Dual Phenotype of MDA-MB-468 Cancer Cells Reveals Mutual Regulation of Tensin3 and Adhesion Plasticity
,”
J. Cell Sci.
,
130
(
13
), pp.
2172
2184
.10.1242/jcs.200899
33.
Polacheck
,
W. J.
,
German
,
A. E.
,
Mammoto
,
A.
,
Ingber
,
D. E.
, and
Kamm
,
R. D.
,
2014
, “
Mechanotransduction of Fluid Stresses Governs 3D Cell Migration
,”
Proc. Natl. Acad. Sci. U.S.A.
,
111
(
7
), pp.
2447
2452
.10.1073/pnas.1316848111
34.
Jones
,
B. C.
,
Kelley
,
L. C.
,
Loskutov
,
Y. V.
,
Marinak
,
K. M.
,
Kozyreva
,
V. K.
,
Smolkin
,
M. B.
, and
Pugacheva
,
E. N.
,
2017
, “
Dual Targeting of Mesenchymal and Amoeboid Motility Hinders Metastatic Behavior
,”
Mol. Cancer Res.
,
15
(
6
), pp.
670
682
.10.1158/1541-7786.MCR-16-0411
35.
Gilkes
,
D. M.
,
Xiang
,
L.
,
Lee
,
S. J.
,
Chaturvedi
,
P.
,
Hubbi
,
M. E.
,
Wirtz
,
D.
, and
Semenza
,
G. L.
,
2014
, “
Hypoxia-Inducible Factors Mediate Coordinated RhoA-ROCK1 Expression and Signaling in Breast Cancer Cells
,”
Proc. Natl. Acad. Sci. U.S.A.
,
111
(
3
), pp.
E384
E393
.10.1073/pnas.1321510111
36.
Mayor
,
R.
, and
Etienne-Manneville
,
S.
,
2016
, “
The Front and Rear of Collective Cell Migration
,”
Nat. Rev. Mol. Cell Biol.
,
17
(
2
), pp.
97
109
.10.1038/nrm.2015.14
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