Tumor progression and response to treatment is determined in large part by the generation of mechanical stresses that stem from both the solid and the fluid phase of the tumor. Furthermore, elevated solid stress levels can regulate fluid stresses by compressing intratumoral blood and lymphatic vessels. Blood vessel compression reduces tumor perfusion, while compression of lymphatic vessels hinders the ability of the tumor to drain excessive fluid from its interstitial space contributing to the uniform elevation of the interstitial fluid pressure. Hypoperfusion and interstitial hypertension pose major barriers to the systemic administration of chemotherapeutic agents and nanomedicines to tumors, reducing treatment efficacies. Hypoperfusion can also create a hypoxic and acidic tumor microenvironment that promotes tumor progression and metastasis. Hence, alleviation of intratumoral solid stress levels can decompress tumor vessels and restore perfusion and interstitial fluid pressure. In this review, three major types of tissue level solid stresses involved in tumor growth, namely stress exerted externally on the tumor by the host tissue, swelling stress, and residual stress, are discussed separately and details are provided regarding their causes, magnitudes, and remedies. Subsequently, evidence of how stress-alleviating drugs could be used in combination with chemotherapy to improve treatment efficacy is presented, highlighting the potential of stress-alleviation strategies to enhance cancer therapy. Finally, a continuum-level, mathematical framework to incorporate these types of solid stress is outlined.

References

References
1.
Hanahan
,
D.
, and
Coussens
,
L. M.
,
2012
, “
Accessories to the Crime: Functions of Cells Recruited to the Tumor Microenvironment
,”
Cancer Cell
,
21
(
3
), pp.
309
322
.
2.
Gkretsi
,
V.
,
Stylianou
,
A.
,
Papageorgis
,
P.
,
Polydorou
,
C.
, and
Stylianopoulos
,
T.
,
2015
, “
Remodeling Components of the Tumor Microenvironment to Enhance Cancer Therapy
,”
Front. Oncol.
,
5
, p.
214
.
3.
Jain
,
R. K.
,
Martin
,
J. D.
, and
Stylianopoulos
,
T.
,
2014
, “
The Role of Mechanical Forces in Tumor Growth and Therapy
,”
Annu. Rev. Biomed. Eng.
,
16
(
1
), pp.
321
346
.
4.
Koumoutsakos
,
P.
,
Pivkin
,
I.
, and
Milde
,
F.
,
2013
, “
The Fluid Mechanics of Cancer and Its Therapy
,”
Annu. Rev. Fluid Mech.
,
45
(
1
), pp.
325
355
.
5.
Voutouri
,
C.
,
Mpekris
,
F.
,
Papageorgis
,
P.
,
Odysseos
,
A. D.
, and
Stylianopoulos
,
T.
,
2014
, “
Role of Constitutive Behavior and Tumor-Host Mechanical Interactions in the State of Stress and Growth of Solid Tumors
,”
PLoS One
,
9
(
8
), p.
e104717
.
6.
Stylianopoulos
,
T.
,
Martin
,
J. D.
,
Snuderl
,
M.
,
Mpekris
,
F.
,
Jain
,
S. R.
, and
Jain
,
R. K.
,
2013
, “
Coevolution of Solid Stress and Interstitial Fluid Pressure in Tumors During Progression: Implications for Vascular Collapse
,”
Cancer Res.
,
73
(
13
), pp.
3833
3841
.
7.
McGrail
,
D. J.
,
McAndrews
,
K. M.
,
Brandenburg
,
C. P.
,
Ravikumar
,
N.
,
Kieu
,
Q. M.
, and
Dawson
,
M. R.
,
2015
, “
Osmotic Regulation Is Required for Cancer Cell Survival Under Solid Stress
,”
Biophys. J.
,
109
(
7
), pp.
1334
1337
.
8.
Voutouri
,
C.
,
Polydorou
,
C.
,
Papageorgis
,
P.
,
Gkretsi
,
V.
, and
Stylianopoulos
,
T.
,
2016
, “
Hyaluronan-Derived Swelling of Solid Tumors, the Contribution of Collagean and Cancer Cells and Implications for Cancer Therapy
,”
Neoplasia
, (to appear).
9.
Stylianopoulos
,
T.
,
Martin
,
J. D.
,
Chauhan
,
V. P.
,
Jain
,
S. R.
,
Diop-Frimpong
,
B.
,
Bardeesy
,
N.
,
Smith
,
B. L.
,
Ferrone
,
C. R.
,
Hornicek
,
F. J.
,
Boucher
,
Y.
,
Munn
,
L. L.
, and
Jain
,
R. K.
,
2012
, “
Causes, Consequences, and Remedies for Growth-Induced Solid Stress in Murine and Human Tumors
,”
Proc. Natl. Acad. Sci. U. S. Am.
,
109
(
38
), pp.
15101
15108
.
10.
Helmlinger
,
G.
,
Netti
,
P. A.
,
Lichtenbeld
,
H. C.
,
Melder
,
R. J.
, and
Jain
,
R. K.
,
1997
, “
Solid Stress Inhibits the Growth of Multicellular Tumor Spheroids
,”
Nat. Biotechnol.
,
15
(
8
), pp.
778
783
.
11.
Kaufman
,
L. J.
,
Brangwynne
,
C. P.
,
Kasza
,
K. E.
,
Filippidi
,
E.
,
Gordon
,
V. D.
,
Deisboeck
,
T. S.
, and
Weitz
,
D. A.
,
2005
, “
Glioma Expansion in Collagen I Matrices: Analyzing Collagen Concentration-Dependent Growth and Motility Patterns
,”
Biophys. J.
,
89
(
1
), pp.
635
650
.
12.
Cheng
,
G.
,
Tse
,
J.
,
Jain
,
R. K.
, and
Munn
,
L. L.
,
2009
, “
Micro-Environmental Mechanical Stress Controls Tumor Spheroid Size and Morphology by Suppressing Proliferation and Inducing Apoptosis in Cancer Cells
,”
PLoS One
,
4
(
2
), p.
e4632
.
13.
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
.
14.
Tse
,
J. M.
,
Cheng
,
G.
,
Tyrrell
,
J. A.
,
Wilcox-Adelman
,
S. A.
,
Boucher
,
Y.
,
Jain
,
R. K.
, and
Munn
,
L. L.
,
2012
, “
Mechanical Compression Drives Cancer Cells Toward Invasive Phenotype
,”
Proc. Natl. Acad. Sci.
,
109
(
3
), pp.
911
916
.
15.
Jain
,
R. K.
,
Tong
,
R. T.
, and
Munn
,
L. L.
,
2007
, “
Effect of Vascular Normalization by Antiangiogenic Therapy on Interstitial Hypertension, Peritumor Edema, and Lymphatic Metastasis: Insights From a Mathematical Model
,”
Cancer Res.
,
67
(
6
), pp.
2729
2735
.
16.
Jain
,
R. K.
,
2014
, “
Antiangiogenesis Strategies Revisited: From Starving Tumors to Alleviating Hypoxia
,”
Cancer Cell
,
26
(
5
), pp.
605
622
.
17.
Facciabene
,
A.
,
Peng
,
X.
,
Hagemann
,
I. S.
,
Balint
,
K.
,
Barchetti
,
A.
,
Wang
,
L. P.
,
Gimotty
,
P. A.
,
Gilks
,
C. B.
,
Lal
,
P.
,
Zhang
,
L.
, and
Coukos
,
G.
,
2011
, “
Tumour Hypoxia Promotes Tolerance and Angiogenesis Via CCL28 and T(reg) Cells
,”
Nature
,
475
(
7355
), pp.
226
230
.
18.
Barsoum
,
I. B.
,
Koti
,
M.
,
Siemens
,
D. R.
, and
Graham
,
C. H.
,
2014
, “
Mechanisms of Hypoxia-Mediated Immune Escape in Cancer
,”
Cancer Res.
,
74
(
24
), pp.
7185
7190
.
19.
Lee
,
K. E.
, and
Simon
,
M. C.
,
2012
, “
From Stem Cells to Cancer Stem Cells: HIF Takes the Stage
,”
Curr. Opin. Cell Biol.
,
24
(
2
), pp.
232
235
.
20.
Samanta
,
D.
,
Gilkes
,
D. M.
,
Chaturvedi
,
P.
,
Xiang
,
L.
, and
Semenza
,
G. L.
,
2014
, “
Hypoxia-Inducible Factors are Required for Chemotherapy Resistance of Breast Cancer Stem Cells
,”
Proc. Natl. Acad. Sci. U. S. A.
,
111
(
50
), p.
E5429-5438
.
21.
Finger
,
E. C.
, and
Giaccia
,
A. J.
,
2010
, “
Hypoxia, Inflammation, and the Tumor Microenvironment in Metastatic Disease
,”
Cancer Metastasis Rev.
,
29
(
2
), pp.
285
293
.
22.
Carmeliet
,
P.
, and
Jain
,
R. K.
,
2011
, “
Molecular Mechanisms and Clinical Applications of Angiogenesis
,”
Nature
,
473
(
7347
), pp.
298
307
.
23.
Batchelor
,
T. T.
,
Gerstner
,
E. R.
,
Emblem
,
K. E.
,
Duda
,
D. G.
,
Kalpathy-Cramer
,
J.
,
Snuderl
,
M.
,
Ancukiewicz
,
M.
,
Polaskova
,
P.
,
Pinho
,
M. C.
,
Jennings
,
D.
,
Plotkin
,
S. R.
,
Chi
,
A. S.
,
Eichler
,
A. F.
,
Dietrich
,
J.
,
Hochberg
,
F. H.
,
Lu-Emerson
,
C.
,
Iafrate
,
A. J.
,
Rosen
,
B.
,
Loeffler
,
J. S.
,
Wen
,
P. Y.
,
Sorensen
,
A. G.
, and
Jain
,
R. K.
,
2013
, “
Improved Tumor Oxygenation and Survival in Glioblastoma Patients Who Show Increased Blood Perfusion After Cediranib and Chemoradiation
,”
Proc. Natl. Acad. Sci. U. S. A.
,
110
(
47
), pp.
19059
19064
.
24.
Jain
,
R. K.
, and
Stylianopoulos
,
T.
,
2010
, “
Delivering Nanomedicine to Solid Tumors
,”
Nat. Rev. Clin. Oncol.
,
7
(
11
), pp.
653
664
.
25.
Chauhan
,
V. P.
,
Stylianopoulos
,
T.
,
Boucher
,
Y.
, and
Jain
,
R. K.
,
2011
, “
Delivery of Molecular and Nanomedicine to Tumors: Transport Barriers and Strategies
,”
Ann. Rev. Chem. Biomol. Eng.
,
2
(
1
), pp.
281
298
.
26.
Samani
,
A.
,
Zubovits
,
J.
, and
Plewes
,
D.
,
2007
, “
Elastic Moduli of Normal and Pathological Human Breast Tissues: An Inversion-Technique-Based Investigation of 169 Samples
,”
Phys. Med. Biol.
,
52
(
6
), pp.
1565
1576
.
27.
Angeli
,
S.
, and
Stylianopoulos
,
T.
,
2016
, “
Biphasic Modeling of Brain Tumor Biomechanics and Response to Radiation Treatment
,”
J. Biomech.
,
49
(
9
), pp.
1524
1531
.
28.
Roose
,
T.
,
Netti
,
P. A.
,
Munn
,
L. L.
,
Boucher
,
Y.
, and
Jain
,
R. K.
,
2003
, “
Solid Stress Generated by Spheroid Growth Estimated Using a Linear Poroelasticity Model
,”
Microvasc. Res.
,
66
(
3
), pp.
204
212
.
29.
Sarntinoranont
,
M.
,
Rooney
,
F.
, and
Ferrari
,
M.
,
2003
, “
Interstitial Stress and Fluid Pressure Within a Growing Tumor
,”
Ann. Biomed. Eng.
,
31
(
3
), pp.
327
335
.
30.
Kim
,
Y.
,
Stolarska
,
M. A.
, and
Othmer
,
H. G.
,
2011
, “
The Role of the Microenvironment in Tumor Growth and Invasion
,”
Progr. Biophys. Mol. Biol.
,
106
(
2
), pp.
353
379
.
31.
Griffon-Etienne
,
G.
,
Boucher
,
Y.
,
Brekken
,
C.
,
Suit
,
H. D.
, and
Jain
,
R. K.
,
1999
, “
Taxane-Induced Apoptosis Decompresses Blood Vessels and Lowers Interstitial Fluid Pressure in Solid Tumors: Clinical Implications
,”
Cancer Res.
,
59
(
15
), pp.
3776
3782
.http://cancerres.aacrjournals.org/content/59/15/3776.long
32.
Padera
,
T. P.
,
Stoll
,
B. R.
,
Tooredman
,
J. B.
,
Capen
,
D.
,
di Tomaso
,
E.
, and
Jain
,
R. K.
,
2004
, “
Pathology: Cancer Cells Compress Intratumour Vessels
,”
Nature
,
427
(
6976
), p.
695
.
33.
Nia
,
H. T.
,
Liu
,
H.
,
Seano
,
G.
,
Datta
,
M.
,
Jones
,
D.
,
Rahbari
,
N.
,
Incio
,
J.
,
Chauhan
,
V. P.
,
Jung
,
K.
,
Martin
,
J. D.
,
Askoxylakis
,
V.
,
Padera
,
T. P.
,
Fukumura
,
D.
,
Boucher
,
Y.
,
Hornicek
,
F. J.
,
Grodzinsky
,
A. J.
,
Baish
,
J. W.
,
Munn
,
L. L.
, and
Jain
,
R. K.
,
2017
, “
Solid Stress and Elastic Energy: new Measures of Tumor Mechanopathology
,”
Nat. Biomed. Eng.
, (to appear).
34.
Netti
,
P. A.
,
Berk
,
D. A.
,
Swartz
,
M. A.
,
Grodzinsky
,
A. J.
, and
Jain
,
R. K.
,
2000
, “
Role of Extracellular Matrix Assembly in Interstitial Transport in Solid Tumors
,”
Cancer Res.
,
60
(
9
), pp.
2497
2503
.http://cancerres.aacrjournals.org/content/60/9/2497
35.
Fung
,
Y. C.
,
1993
,
Biomechanics: Mechanical Properties of Living Tissues
,
Spinger-Verlag
,
New York
.
36.
Ferguson
,
S. J.
,
Ito
,
K.
, and
Nolte
,
L. P.
,
2004
, “
Fluid Flow and Convective Transport of Solutes Within the Intervertebral Disc
,”
J. Biomech.
,
37
(
2
), pp.
213
221
.
37.
Ambrosi
,
D.
, and
Mollica
,
F.
,
2002
, “
On the Mechanics of a Growing Tumor
,”
Int. J. Eng. Sci.
,
40
(
12
), pp.
1297
1316
.
38.
MacLaurin
,
J.
,
Chapman
,
J.
,
Jones
,
G. W.
, and
Roose
,
T.
,
2012
, “
The Buckling of Capillaries in Solid Tumours
,”
Proc. R. Soc. A
,
468
(
2148
), pp.
4123
4145
.
39.
Ciarletta
,
P.
,
2013
, “
Buckling Instability in Growing Tumor Spheroids
,”
Phys. Rev. Lett.
,
110
(
15
), p.
158102
.
40.
Delarue
,
M.
,
Montel
,
F.
,
Vignjevic
,
D.
,
Prost
,
J.
,
Joanny
,
J. F.
, and
Cappello
,
G.
,
2014
, “
Compressive Stress Inhibits Proliferation in Tumor Spheroids Through a Volume Limitation
,”
Biophys. J.
,
107
(
8
), pp.
1821
1828
.
41.
Desmaison
,
A.
,
Frongia
,
C.
,
Grenier
,
K.
,
Ducommun
,
B.
, and
Lobjois
,
V.
,
2013
, “
Mechanical Stress Impairs Mitosis Progression in Multi-Cellular Tumor Spheroids
,”
PLoS One
,
8
(
12
), p.
e80447
.
42.
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
.
43.
Eisenberg
,
S. R.
, and
Grodzinsky
,
A. J.
,
1985
, “
Swelling of Articular Cartilage and Other Connective Tissues: Electromechanochemical Forces
,”
J. Orthop. Res. Off. Publ. Orthop. Res. Soc.
,
3
(
2
), pp.
148
159
.
44.
Lai
,
V. K.
,
Nedrelow
,
D. S.
,
Lake
,
S. P.
,
Kim
,
B.
,
Weiss
,
E. M.
,
Tranquillo
,
R. T.
, and
Barocas
,
V. H.
,
2016
, “
Swelling of Collagen-Hyaluronic Acid Co-Gels: An In Vitro Residual Stress Model
,”
Ann. Biomed. Eng.
,
44
(
1
), pp.
2984
2993
.
45.
Choung
,
C. J.
, and
Fung
,
Y. C.
,
1986
, “
Residual Stress in Arteries
,”
Frontiers in Biomechanics
,
G. W.
Schmid-Schoenbein
,
S. L.
Woo
, and
B. W.
Zweifach
, eds.,
Springer
,
New York
, pp.
117
129
.
46.
Liu
,
S. Q.
, and
Fung
,
Y. C.
,
1988
, “
Zero-Stress States of Arteries
,”
ASME J. Biomech. Eng.
,
110
(
1
), pp.
82
84
.
47.
Omens
,
J. H.
, and
Fung
,
Y. C.
,
1990
, “
Residual Strain in Rat Left Ventricle
,”
Circ. Res.
,
66
(
1
), pp.
37
45
.
48.
Taber
,
L. A.
, and
Humphrey
,
J. D.
,
2001
, “
Stress-Modulated Growth, Residual Stress, and Vascular Heterogeneity
,”
ASME J. Biomech. Eng.
,
123
(
6
), pp.
528
535
.
49.
Omens
,
J. H.
,
Vaplon
,
S. M.
,
Fazeli
,
B.
, and
McCulloch
,
A. D.
,
1998
, “
Left Ventricular Geometric Remodeling and Residual Stress in the Rat Heart
,”
ASME J. Biomech. Eng.
,
120
(
6
), pp.
715
719
.
50.
Xu
,
G.
,
Bayly
,
P. V.
, and
Taber
,
L. A.
,
2009
, “
Residual Stress in the Adult Mouse Brain
,”
Biomech. Model. Mechanobiol.
,
8
(
4
), pp.
253
262
.
51.
Skalak
,
R.
,
Zargaryan
,
S.
,
Jain
,
R. K.
,
Netti
,
P. A.
, and
Hoger
,
A.
,
1996
, “
Compatibility and the Genesis of Residual Stress by Volumetric Growth
,”
J. Math. Biol.
,
34
(
8
), pp.
889
914
.
52.
Omens
,
J. H.
,
McCulloch
,
A. D.
, and
Criscione
,
J. C.
,
2003
, “
Complex Distributions of Residual Stress and Strain in the Mouse Left Ventricle: Experimental and Theoretical Models
,”
Biomech. Model. Mechanobiol.
,
1
(
4
), pp.
267
277
.
53.
Ren
,
J. S.
,
2013
, “
Growth and Residual Stresses of Arterial Walls
,”
J. Theor. Biol.
,
337
, pp.
80
88
.
54.
Hagendoorn
,
J.
,
Tong
,
R.
,
Fukumura
,
D.
,
Lin
,
Q.
,
Lobo
,
J.
,
Padera
,
T. P.
,
Xu
,
L.
,
Kucherlapati
,
R.
, and
Jain
,
R. K.
,
2006
, “
Onset of Abnormal Blood and Lymphatic Vessel Function and Interstitial Hypertension in Early Stages of Carcinogenesis
,”
Cancer Res.
,
66
(
7
), pp.
3360
3364
.
55.
Boucher
,
Y.
,
Baxter
,
L. T.
, and
Jain
,
R. K.
,
1990
, “
Interstitial Pressure Gradients in Tissue-Isolated and Subcutaneous Tumors: Implications for Therapy
,”
Cancer Res.
,
50
(
15
), pp.
4478
4484
.http://cancerres.aacrjournals.org/content/50/15/4478
56.
Boucher
,
Y.
, and
Jain
,
R. K.
,
1992
, “
Microvascular Pressure Is the Principal Driving Force for Interstitial Hypertension in Solid Tumors: Implications for Vascular Collapse
,”
Cancer Res.
,
52
(
18
), pp.
5110
5114
.http://cancerres.aacrjournals.org/content/52/18/5110
57.
Chauhan
,
V. P.
,
Stylianopoulos
,
T.
,
Martin
,
J. D.
,
Popovic
,
Z.
,
Chen
,
O.
,
Kamoun
,
W. S.
,
Bawendi
,
M. G.
,
Fukumura
,
D.
, and
Jain
,
R. K.
,
2012
, “
Normalization of Tumour Blood Vessels Improves the Delivery of Nanomedicines in a Size-Dependent Manner
,”
Nat. Nanotechnol.
,
7
(
6
), pp.
383
388
.
58.
Popovic
,
Z.
,
Liu
,
W.
,
Chauhan
,
V. P.
,
Lee
,
J.
,
Wong
,
C.
,
Greytak
,
A. B.
,
Insin
,
N.
,
Nocera
,
D. G.
,
Fukumura
,
D.
,
Jain
,
R. K.
, and
Bawendi
,
M. G.
,
2010
, “
A Nanoparticle Size Series for In Vivo Fluorescence Imaging
,”
Angew. Chem. Int. Ed. Engl.
,
49
(
46
), pp.
8649
8652
.
59.
Stylianopoulos
,
T.
, and
Jain
,
R. K.
,
2015
, “
Design Considerations for Nanotherapeutics in Oncology
,”
Nanomed. Nanotechnol., Biol. Med.
,
11
(
8
), pp.
1893
1907
.
60.
Baxter
,
L. T.
, and
Jain
,
R. K.
,
1989
, “
Transport of Fluid and Macromolecules in Tumors—I: Role of Interstitial Pressure and Convection
,”
Microvasc. Res.
,
37
(
1
), pp.
77
104
.
61.
Baxter
,
L. T.
, and
Jain
,
R. K.
,
1990
, “
Transport of Fluid and Macromolecules in Tumors—II: Role of Heterogeneous Perfusion and Lymphatics
,”
Microvasc. Res.
,
40
(
2
), pp.
246
263
.
62.
Chauhan
,
V. P.
,
Martin
,
J. D.
,
Liu
,
H.
,
Lacorre
,
D. A.
,
Jain
,
S. R.
,
Kozin
,
S. V.
,
Stylianopoulos
,
T.
,
Mousa
,
A.
,
Han
,
X.
,
Adstamongkonkul
,
P.
,
Popovic
,
Z.
,
Bawendi
,
M. G.
,
Boucher
,
Y.
, and
Jain
,
R. K.
,
2013
, “
Angiotensin Inhibition Enhances Drug Delivery and Potentiates Chemotherapy by Decompressing Tumor Blood Vessels
,”
Nat. Commun.
,
4
, p.
2516
.
63.
Jain
,
R. K.
,
2014
, “
An Indirect Way to Tame Cancer
,”
Sci. Am.
,
310
(
2
), pp.
46
53
.
64.
Stylianopoulos
,
T.
, and
Jain
,
R. K.
,
2013
, “
Combining Two Strategies to Improve Perfusion and Drug Delivery in Solid Tumors
,”
Proc. Natl. Acad. Sci. U. S. A.
,
110
(
46
), pp.
18632
18637
.
65.
Perentes
,
J. Y.
,
McKee
,
T. D.
,
Ley
,
C. D.
,
Mathiew
,
H.
,
Dawson
,
M.
,
Padera
,
T. P.
,
Munn
,
L. L.
,
Jain
,
R. K.
, and
Boucher
,
Y.
,
2009
, “
In Vivo Imaging of Extracellular Matrix Remodeling by Tumor-Associated Fibroblasts
,”
Nat. Methods
,
6
(
2
), pp.
143
145
.
66.
Olive
,
K. P.
,
Jacobetz
,
M. A.
,
Davidson
,
C. J.
,
Gopinathan
,
A.
,
McIntyre
,
D.
,
Honess
,
D.
,
Madhu
,
B.
,
Goldgraben
,
M. A.
,
Caldwell
,
M. E.
,
Allard
,
D.
,
Frese
,
K. K.
,
Denicola
,
G.
,
Feig
,
C.
,
Combs
,
C.
,
Winter
,
S. P.
,
Ireland-Zecchini
,
H.
,
Reichelt
,
S.
,
Howat
,
W. J.
,
Chang
,
A.
,
Dhara
,
M.
,
Wang
,
L.
,
Ruckert
,
F.
,
Grutzmann
,
R.
,
Pilarsky
,
C.
,
Izeradjene
,
K.
,
Hingorani
,
S. R.
,
Huang
,
P.
,
Davies
,
S. E.
,
Plunkett
,
W.
,
Egorin
,
M.
,
Hruban
,
R. H.
,
Whitebread
,
N.
,
McGovern
,
K.
,
Adams
,
J.
,
Iacobuzio-Donahue
,
C.
,
Griffiths
,
J.
, and
Tuveson
,
D. A.
,
2009
, “
Inhibition of Hedgehog Signaling Enhances Delivery of Chemotherapy in a Mouse Model of Pancreatic Cancer
,”
Science
,
324
(
5933
), pp.
1457
1461
.
67.
Hidalgo
,
M.
, and
Von Hoff
,
D. D.
,
2012
, “
Translational Therapeutic Opportunities in Ductal Adenocarcinoma of the Pancreas
,”
Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res.
,
18
(
16
), pp.
4249
4256
.
68.
Diop-Frimpong
,
B.
,
Chauhan
,
V. P.
,
Krane
,
S.
,
Boucher
,
Y.
, and
Jain
,
R. K.
,
2011
, “
Losartan Inhibits Collagen I Synthesis and Improves the Distribution and Efficacy of Nanotherapeutics in Tumors
,”
Proc. Natl. Acad. Sci. U. S. A.
,
108
(
7
), pp.
2909
2914
.
69.
Wilop
,
S.
,
von Hobe
,
S.
,
Crysandt
,
M.
,
Esser
,
A.
,
Osieka
,
R.
, and
Jost
,
E.
,
2009
, “
Impact of Angiotensin I Converting Enzyme Inhibitors and Angiotensin II Type 1 Receptor Blockers on Survival in Patients With Advanced Non-Small-Cell Lung Cancer Undergoing First-Line Platinum-Based Chemotherapy
,”
J. Cancer Res. Clin. Oncol.
,
135
(
10
), pp.
1429
1435
.
70.
Nakai
,
Y.
,
Isayama
,
H.
,
Ijichi
,
H.
,
Sasaki
,
T.
,
Sasahira
,
N.
,
Hirano
,
K.
,
Kogure
,
H.
,
Kawakubo
,
K.
,
Yagioka
,
H.
,
Yashima
,
Y.
,
Mizuno
,
S.
,
Yamamoto
,
K.
,
Arizumi
,
T.
,
Togawa
,
O.
,
Matsubara
,
S.
,
Tsujino
,
T.
,
Tateishi
,
K.
,
Tada
,
M.
,
Omata
,
M.
, and
Koike
,
K.
,
2010
, “
Inhibition of Renin-Angiotensin System Affects Prognosis of Advanced Pancreatic Cancer Receiving Gemcitabine
,”
Br. J. Cancer
,
103
(
11
), pp.
1644
1648
.
71.
Keizman
,
D.
,
Huang
,
P.
,
Eisenberger
,
M. A.
,
Pili
,
R.
,
Kim
,
J. J.
,
Antonarakis
,
E. S.
,
Hammers
,
H.
, and
Carducci
,
M. A.
,
2011
, “
Angiotensin System Inhibitors and Outcome of Sunitinib Treatment in Patients With Metastatic Renal Cell Carcinoma: A Retrospective Examination
,”
Eur. J. Cancer (Oxford, England: 1990)
,
47
(
13
), pp.
1955
1961
.
72.
Nakai
,
Y.
,
Isayama
,
H.
,
Ijichi
,
H.
,
Sasaki
,
T.
,
Kogure
,
H.
,
Yagioka
,
H.
,
Miyabayashi
,
K.
,
Mizuno
,
S.
,
Yamamoto
,
K.
,
Mouri
,
D.
,
Kawakubo
,
K.
,
Yamamoto
,
N.
,
Hirano
,
K.
,
Sasahira
,
N.
,
Tateishi
,
K.
,
Tada
,
M.
, and
Koike
,
K.
,
2012
, “
Phase I Trial of Gemcitabine and Candesartan Combination Therapy in Normotensive Patients With Advanced Pancreatic Cancer: GECA1
,”
Cancer Sci.
,
103
(
8
), pp.
1489
1492
.
73.
Jacobetz
,
M. A.
,
Chan
,
D. S.
,
Neesse
,
A.
,
Bapiro
,
T. E.
,
Cook
,
N.
,
Frese
,
K. K.
,
Feig
,
C.
,
Nakagawa
,
T.
,
Caldwell
,
M. E.
,
Zecchini
,
H. I.
,
Lolkema
,
M. P.
,
Jiang
,
P.
,
Kultti
,
A.
,
Thompson
,
C. B.
,
Maneval
,
D. C.
,
Jodrell
,
D. I.
,
Frost
,
G. I.
,
Shepard
,
H. M.
,
Skepper
,
J. N.
, and
Tuveson
,
D. A.
,
2012
, “
Hyaluronan Impairs Vascular Function and Drug Delivery in a Mouse Model of Pancreatic Cancer
,”
Gut
,
62
(
1
), pp.
112
120
.
74.
Provenzano
,
P. P.
,
Cuevas
,
C.
,
Chang
,
A. E.
,
Goel
,
V. K.
,
Von Hoff
,
D. D.
, and
Hingorani
,
S. R.
,
2012
, “
Enzymatic Targeting of the Stroma Ablates Physical Barriers to Treatment of Pancreatic Ductal Adenocarcinoma
,”
Cancer Cell
,
21
(
3
), pp.
418
429
.
75.
Liu
,
J.
,
Liao
,
S.
,
Diop-Frimpong
,
B.
,
Chen
,
W.
,
Goel
,
S.
,
Naxerova
,
K.
,
Ancukiewicz
,
M.
,
Boucher
,
Y.
,
Jain
,
R. K.
, and
Xu
,
L.
,
2012
, “
TGF-Beta Blockade Improves the Distribution and Efficacy of Therapeutics in Breast Carcinoma by Normalizing the Tumor Stroma
,”
Proc. Natl. Acad. Sci. U. S. A.
,
109
(
41
), pp.
16618
16623
.
76.
Papageorgis
,
P.
, and
Stylianopoulos
,
T.
,
2015
, “
Role of TGFbeta in Regulation of the Tumor Microenvironment and Drug Delivery (Review)
,”
Int. J. Oncol.
,
46
(
3
), pp.
933
943
.
77.
Papageorgis
,
P.
,
Polydorou
,
C.
,
Mpekris
,
F.
,
Voutouri
,
C.
,
Eliana
,
C.
,
Kapnisi
,
C.
, and
Stylianopoulos
,
T.
,
2016
, “
Tranilast-Induced Stress Alleviation Improves the Efficacy of Anti-Cancer Drugs in a Size-Independent Manner
,” (submitted).
78.
Stockmann
,
C.
,
Doedens
,
A.
,
Weidemann
,
A.
,
Zhang
,
N.
,
Takeda
,
N.
,
Greenberg
,
J. I.
,
Cheresh
,
D. A.
, and
Johnson
,
R. S.
,
2008
, “
Deletion of Vascular Endothelial Growth Factor in Myeloid Cells Accelerates Tumorigenesis
,”
Nature
,
456
(
7223
), pp.
814
818
.
79.
Rhim
,
A. D.
,
Mirek
,
E. T.
,
Aiello
,
N. M.
,
Maitra
,
A.
,
Bailey
,
J. M.
,
McAllister
,
F.
,
Reichert
,
M.
,
Beatty
,
G. L.
,
Rustgi
,
A. K.
,
Vonderheide
,
R. H.
,
Leach
,
S. D.
, and
Stanger
,
B. Z.
,
2012
, “
EMT and Dissemination Precede Pancreatic Tumor Formation
,”
Cell
,
148
(
1–2
), pp.
349
361
.
80.
Rodriguez
,
E. K.
,
Hoger
,
A.
, and
McCulloch
,
A. D.
,
1994
, “
Stress-Dependent Finite Growth in Soft Elastic Tissues
,”
J. Biomech.
,
27
(
4
), pp.
455
467
.
81.
Mpekris
,
F.
,
Angeli
,
S.
,
Pirentis
,
A. P.
, and
Stylianopoulos
,
T.
,
2015
, “
Stress-Mediated Progression of Solid Tumors: Effect of Mechanical Stress on Tissue Oxygenation, Cancer Cell Proliferation, and Drug Delivery
,”
Biomech. Model. Mechanobiol.
,
14
(
6
), pp.
1391
1402
.
82.
Voutouri
,
C.
, and
Stylianopoulos
,
T.
,
2014
, “
Evolution of Osmotic Pressure in Solid Tumors
,”
J. Biomech.
,
47
(
14
), pp.
3441
3447
.
83.
Sun
,
D. N.
,
Gu
,
W. Y.
,
Guo
,
X. E.
,
Lai
,
W. M.
, and
Mow
,
V. C.
,
1999
, “
A Mixed Finite Element Formulation of Triphasic Mechano-Electrochemical Theory for Charged, Hydrated Biological Soft Tissues
,”
Int. J. Numer. Methods Eng.
,
45
(
10
), pp.
1375
1402
.
84.
Lu
,
X. L.
,
Wan
,
L. Q.
,
Guo
,
X. E.
, and
Mow
,
V. C.
,
2010
, “
A Linearized Formulation of Triphasic Mixture Theory for Articular Cartilage, and its Application to Indentation Analysis
,”
J. Biomech.
,
43
(
4
), pp.
673
679
.
85.
Ambrosi
,
D.
, and
Preziosi
,
L.
,
2009
, “
Cell Adhesion Mechanisms and Stress Relaxation in the Mechanics of Tumours
,”
Biomech. Model. Mechanobiol.
,
8
(
5
), pp.
397
413
.
86.
Taber
,
L. A.
,
2008
, “
Theoretical Study of Beloussov's Hyper-Restoration Hypothesis for Mechanical Regulation of Morphogenesis
,”
Biomech. Model. Mechanobiol.
,
7
(
6
), pp.
427
441
.
87.
Stylianopoulos
,
T.
, and
Barocas
,
V. H.
,
2007
, “
Volume Averaging Theory for the Study of the Mechanics of Collagen Networks
,”
Comput. Methods Appl. Mech. Eng.
,
196
(
31–32
), pp.
2981
2990
.
88.
Wijeratne
,
P. A.
,
Vavourakis
,
V.
,
Hipwell
,
J. H.
,
Voutouri
,
C.
,
Papageorgis
,
P.
,
Stylianopoulos
,
T.
,
Evans
,
A.
, and
Hawkes
,
D. J.
,
2016
, “
Multiscale Modelling of Solid Tumour Growth: the Effect of Collagen Micromechanics
,”
Biomech. Model. Mechanobiol.
,
15
(
5
), pp.
1079
1090
.
89.
Pirentis
,
A. P.
,
Polydorou
,
C.
,
Papageorgis
,
P.
,
Voutouri
,
C.
,
Mpekris
,
F.
, and
Stylianopoulos
,
T.
,
2015
, “
Remodeling of Extracellular Matrix Due to Solid Stress Accumulation During Tumor Growth
,”
Connect. Tissue Res.
,
56
(
5
), pp.
345
354
.
90.
Ramirez-Torres
,
A.
,
Rodriguez-Ramos
,
R.
,
Merodio
,
J.
,
Bravo-Castillero
,
J.
,
Guinovart-Diaz
,
R.
, and
Alfonso
,
J. C. L.
,
2015
, “
Mathematical Modeling of Anisotropic Avascular Tumor Growth
,”
Mech. Res. Commun.
,
69
, pp.
8
14
.
91.
Giverso
,
C.
, and
Preziosi
,
L.
,
2013
, “
Behavior of Cell Aggregates Under Force-Controlled Compression
,”
Int. J. Nonlinear. Mech.
,
56
, pp.
50
55
.
You do not currently have access to this content.