Elevated total tissue pressure (TTP) in pancreatic adenocarcinoma is often associated with stress applied by cellular proliferation and hydrated hyaluronic acid osmotic swelling; however, the causal roles of collagen in total tissue pressure have yet to be clearly measured. This study illustrates one direct correlation between total tissue pressure and increased deposition of collagen within the tissue matrix. This observation comes from a new modification to a conventional piezoelectric pressure catheter, used to independently separate and quantify total tissue pressure, solid stress (SS), and interstitial fluid pressure (IFP) within the same tumor location, thereby clarifying the relationship between these parameters. Additionally, total tissue pressure shows a direct correlation with verteporfin uptake, demonstrating the impediment of systemically delivered molecules with increased tissue hypertension.

References

References
1.
Howlader
,
N.
,
Noone
,
A. M.
,
Krapcho
,
M.
,
Garshell
,
J.
,
Miller
,
D.
,
Altekruse
,
S. F.
,
Kosary
,
C. L.
,
Yu
,
M.
,
Ruhl
,
J.
,
Tatalovich
,
Z.
,
Mariotto
,
A.
,
Lewis
,
D. R.
,
Chen
,
H. S.
,
Feuer
,
E. J.
, and
Cronin
,
K. A.
,
2015
, “
SEER Cancer Statistics Review, 1975-2012
,” Cronin, K. A., ed.,
National Cancer Institute
, Bethesda, MD.
2.
Freelove
,
R.
, and
Walling
,
A.
,
2006
, “
Pancreatic Cancer: Diagnosis and Management
,”
Am. Fam. Physician
,
73
(
3
), pp.
485
492
.
3.
Carr
,
R. M.
, and
Fernandez-Zapico
,
M. E.
,
2016
, “
Pancreatic Cancer Microenviorment, to Target or Not to Target
,”
EMBO Mol. Med.
,
8
(
2
), pp.
80
82
.
4.
Trouilloud
,
I.
,
Dubreuil
,
O.
,
Boussaha
,
T.
,
Lepere
,
C.
,
Landi
,
B.
,
Zaanan
,
A.
,
Bachet
,
J. B.
, and
Taieb
,
J.
,
2011
, “
Medical Treatment of Pancreatic Cancer: New Hopes After 10 Years of Gemcitabine
,”
Clin. Res. Hepatol. Gastroenterol.
,
35
(
5
), pp.
364
374
.
5.
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
.
6.
Vonlaufen
,
A.
,
Joshi
,
S.
,
Qu
,
C.
,
Phillips
,
P. A.
,
Xu
,
Z.
,
Parker
,
N. R.
,
Toi
,
C. S.
,
Pirola
,
R. C.
,
Wilson
,
J. S.
,
Goldstein
,
D.
, and
Apte
,
M. V.
,
2008
, “
Pancreatic Stellate Cells: Partners in Crime With Pancreatic Cancer Cells
,”
Cancer Res.
,
68
(
7
), pp.
2085
2093
.
7.
Mueller
,
M. M.
, and
Fusenig
,
N. E.
,
2004
, “
Friends or Foes—Bipolar Effects of the Tumour Stroma in Cancer
,”
Nat. Rev. Cancer
,
4
(
11
), pp.
839
849
.
8.
Stylianopoulos
,
T.
,
Martin
,
J. D.
,
Chauhan
,
V. P.
,
Jain
,
S. R.
,
Diop-Frimpog
,
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. A.
,
109
(
38
), pp.
15101
15108
.
9.
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
.
10.
Chauhan
,
V. P.
,
Martin
,
J. D.
,
Liu
,
H.
,
Lacorre
,
D. A.
,
Jain
,
S. R.
,
Kozin
,
S. V.
,
Stylianopoulos
,
T.
,
Mousa
,
A. S.
,
Han
,
X.
,
Adstamongkonkul
,
P.
,
Popovic
,
Z.
,
Huang
,
P.
,
Bawendi
,
M. G.
,
Boucher
,
Y.
, and
Jain
,
R. K.
,
2013
, “
Angiotensin Inhibition Enhances Drug Delivery and Potentiates Chemotherapy by Decompressing Tumour Blood Vessels
,”
Nat. Commun.
,
4
, p.
2516
.
11.
Chauhan
,
V. P.
,
Stylianopoulos
,
T.
,
Boucher
,
Y.
, and
Jain
,
R. K.
,
2011
, “
Delivery of Molecular and Nanoscale Medicine to Tumors: Transport Barriers and Strategies
,”
Annu. Rev. Chem. Biomol. Eng.
,
2
(
1
), pp.
281
298
.
12.
Theocharis
,
A. D.
,
Tsara
,
M. E.
,
Papageorgacopoulou
,
N.
,
Karavias
,
D. D.
, and
Theocharis
,
D. A.
,
2000
, “
Pancreatic Carcinoma is Characterized by Elevated Content of Hyaluronan and Chondroitin Sulfate With Altered Disaccharide Composition
,”
Biochim. Biophys. Acta
,
1502
(
2
), pp.
201
206
.
13.
Lai
,
W. M.
,
Hou
,
J. S.
, and
Mow
,
V. C.
,
1991
, “
A Triphasic Theory for the Swelling and Deformation Behaviors of Articular Cartilage
,”
ASME J. Biomech. Eng.
,
113
(
3
), pp.
245
258
.
14.
Brace
,
R. A.
, and
Guyton
,
A. C.
,
1979
, “
Interstitial Fluid Pressure: Capsule, Free Fluid, Gel Fluid, and Gel Absorption Pressure in Subcutaneous Tissue
,”
Microvasc. Res.
,
18
(
2
), pp.
217
228
.
15.
Mow
,
V. C.
,
Kuei
,
S. C.
,
Lai
,
W. M.
, and
Armstrong
,
C. G.
,
1980
, “
Biphasic Creep and Stress Relaxation of Articular Cartilage in Compression: Theory and Experiments
,”
J. Biomech., Eng.
,
102
(
1
), pp.
73
84
.
16.
DelGiorno
,
K. E.
,
Carlson
,
M. A.
,
Osgood
,
R.
,
Provenzano
,
P. P.
,
Brockenbough
,
J. S.
,
Thompson
,
C. B.
,
Shepard
,
H. M.
,
Frost
,
G. I.
,
Potter
,
J. D.
, and
Hingorani
,
S. R.
,
2014
, “
Response to Chauhan et al: Interstitial Pressure and Vascular Collapse in Pancreas Cancer-Fluids and Solids, Measurement and Meaning
,”
Cancer Cell
,
26
(
1
), pp.
16
17
.
17.
Provenzano
,
P. P.
, and
Hingorani
,
S. R.
,
2013
, “
Hyaluronan, Fluid Pressure, and Stromal Resistance in Pancreas Cancer
,”
Br. J. Cancer
,
108
(
1
), pp.
1
8
.
18.
Chauhan
,
V. P.
,
Boucher
,
Y.
,
Ferrone
,
C. R.
,
Roberge
,
S.
,
Martin
,
J. D.
,
Stylianopoulos
,
T.
,
Bardeesy
,
N.
,
DePinho
,
R. A.
,
Padera
,
T. P.
,
Munn
,
L. L.
, and
Jain
,
R. K.
,
2014
, “
Compression of Pancreatic Tumor Blood Vessels by Hyaluronan is Caused by Solid Stress and Not Interstitial Fluid Pressure
,”
Cancer Cell
,
26
(
1
), pp.
14
15
.
19.
Terzaghi
,
K.
,
1923
, “
Die Berechnung der Durchlässigkeitsziffer des Tones aus dem Verlauf der hydrodynamischen Spannungserscheinungen (A Method of Calculating the Permeability of Clay From the History of Hydrodynamic Stress Variation)
,”
Sitzungsber. d. Akad. d. Wiss., Wien Math. Naturwiss. Kl., Abt. IIa
,
132
, p.
125138
.
20.
Ozerdem
,
U.
,
2009
, “
Measuring Interstitial Fluid Pressure With Fiberoptic Pressure Transducers
,”
Microvasc. Res.
,
77
(
2
), pp.
226
229
.
21.
DuFort
,
C. C.
,
DelGiorno
,
K. E.
,
Carlson
,
M. A.
,
Osgood
,
R. J.
,
Zhao
,
C.
,
Huang
,
Z.
,
Thompson
,
C. B.
,
Connor
,
R. J.
,
Thanos
,
C. D.
,
Brockenbough
,
J. S.
,
Provenzano
,
P. P.
,
Frost
,
G. I.
,
Shepard
,
H. M.
, and
Hingorani
,
S. R.
,
2016
, “
Interstitial Pressure in Pancreatic Ductal Adenocarcinoma is Dominated by a Gel-Fluid Phase
,”
Biophys. J.
,
110
(
9
), pp.
2106
2119
.
22.
Fadnes
,
H. O.
,
Reed
,
R. K.
, and
Aukland
,
K.
,
1977
, “
Interstitial Fluid Pressure in Rats Measured With a Modified Wick Technique
,”
Microvasc. Res.
,
14
(
1
), pp.
27
36
.
23.
Fukumura
,
D.
, and
Jain
,
R. K.
,
2007
, “
Tumor Microvasculature and Microenvironment: Targets for Anti-Angiogenesis and Normalization
,”
Microvasc. Res.
,
74
(
2–3
), pp.
72
84
.
24.
Pakalniskis
,
M. G.
,
Wells
,
W. A.
,
Schwab
,
M. C.
,
Froehlich
,
H. M.
,
Jiang
,
S.
,
Li
,
Z.
,
Tosteson
,
T. D.
,
Poplack
,
S. P.
,
Kaufman
,
P. A.
,
Pogue
,
B. W.
, and
Paulsen
,
K. D.
,
2011
, “
Tumor Angiogenesis Change Estimated by Using Diffuse Optical Spectroscopic Tomography: Demonstrated Correlation in Women Undergoing Neoadjuvant Chemotherapy for Invasive Breast Cancer?
,”
Radiology
,
259
(
2
), pp.
365
374
.
25.
Samkoe
,
K. S.
,
Chen
,
A.
,
Rizvi
,
I.
,
O'Hara
,
J. A.
,
Hoopes
,
P. J.
,
Pereira
,
S. P.
,
Hasan
,
T.
, and
Pogue
,
B. W.
,
2010
, “
Imaging Tumor Variation in Response to Photodynamic Therapy in Pancreas Cancer Xenograft Models
,”
Int. J. Radiat. Oncol. Biol. Phys.
,
76
(
1
), pp.
251
259
.
26.
Dolmans
,
D.
,
Fukumura
,
D.
, and
Jain
,
R. K.
,
2003
, “
Photodynamic Therapy for Cancer
,”
Nat. Rev. Cancer
,
3
(
5
), pp.
380
387
.
27.
Kanick
,
S. C.
,
Davis
,
S. C.
,
Zhao
,
Y.
,
Hasan
,
T.
,
Maytin
,
E. V.
,
Pogue
,
B. W.
, and
Chapman
,
M. S.
,
2014
, “
Dual-Channel Red/Blue Fluorescence Dosimetry With Broadband Reflectance Spectroscopic Correction Measures Protoporphyrin IX Production During Photodynamic Therapy of Actinic Keratosis
,”
J. Biomed. Opt.
,
19
(
7
), p.
075002
.
28.
De Smedt
,
S. C.
,
Lauwers
,
A.
,
Demeester
,
J.
,
Engleborghs
,
Y.
,
De Mey
,
G.
, and
Du
,
M.
,
1994
, “
Structural Information on Hyaluronic Acid Solutions as Studied by Probe Diffusion Experiments
,”
Macromolecules
,
27
(
1
), pp.
141
146
.
29.
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
.
30.
Dewhirst
,
M. W.
,
Braun
,
R. D.
, and
Lanzen
,
J. L.
,
1998
, “
Temporal Changes in PO2 of R3230AC Tumors in Fischer-344 Rats
,”
Int. J. Radiat. Oncol. Biol. Phys.
,
42
(
4
), pp.
723
726
.
31.
Schedin
,
P.
, and
Keely
,
P. J.
,
2011
, “
Mammary Gland ECM Remodeling, Stiffness, and Mechanosignaling in Normal Development and Tumor Progression
,”
CSH Perspect. Biol.
,
3
(
1
), p.
A003228
.
32.
Heldin
,
C. H.
,
Rubin
,
K.
,
Pietras
,
K.
, and
Ostman
,
A.
,
2004
, “
High Interstitial Fluid Pressure—An Obstacle in Cancer Therapy
,”
Nat. Rev. Cancer
,
4
(
10
), pp.
806
813
.
33.
Deer
,
E. L.
,
Gonzalez-Hernandez
,
J.
,
Coursen
,
J. D.
,
Shea
,
J. E.
,
Ngatia
,
J.
,
Scaife
,
C. L.
,
Firpo
,
M. A.
, and
Mulvihill
,
S. J.
,
2010
, “
Phenotype and Genotype of Pancreatic Cancer Cell Lines
,”
Pancreas
,
39
(
4
), pp.
425
435
.
34.
Roeder
,
B. A.
,
Kokini
,
K.
,
Sturgis
,
J. E.
,
Robinson
,
J. P.
, and
Voytik-Harbin
,
S. L.
,
2002
, “
Tensile Mechanical Properties of Three-Dimensional Type I Collagen Extracellular Matrices With Varied Microstructure
,”
ASME J. Biomech. Eng.
,
124
(
2
), p.
214
.
35.
Provenzano
,
P. P.
,
Inman
,
D. R.
,
Eliceiri
,
K. W.
, and
Keely
,
P. J.
,
2009
, “
Matrix Density-Induced Mechanoregulation of Breast Cell Phenotype, Signaling and Gene Expression Through a FAK-ERK Linkage
,”
Oncogene
,
28
(
49
), pp.
4326
4343
.
36.
Gade
,
T. P.
,
Buchanan
,
I. M.
,
Motley
,
M. W.
,
Mazaheri
,
Y.
,
Spees
,
W. M.
, and
Koutcher
,
J. A.
,
2009
, “
Imaging Intratumoral Convection: Pressure-Dependent Enhancement in Chemotherapeutic Delivery to Solid Tumors
,”
Clin. Cancer Res.
,
15
(
1
), pp.
247
255
.
37.
Eikenes
,
L.
,
Bruland
,
O. S.
,
Brekken
,
C.
, and
De Lange Davies
,
C.
,
2004
, “
Collagenase Increased the Transcapillary Gradient and Improves Uptake and Distribution of Monoclonal Antibodies in Human Osteosarcoma Xenografts
,”
Cancer Res.
,
64
(
14
), pp.
4768
4773
.
38.
Tufto
,
I.
,
Hansen
,
R.
,
Byberg
,
D.
,
Nygaard
,
K. H. H.
,
Tufto
,
J.
, and
Davies
,
C. D. L.
,
2007
, “
The Effect of Collagenase and Hyaluronidase on Transient Perfusion in Human Osteosarcoma Xenografts Grown Orthotopically and in Dorsal Skinfold Chamber
,”
Anticancer Res.
,
27
, pp.
1475
1482
.
39.
Olive
,
K. P.
,
Jacobetz
,
M. A.
,
Davidson
,
C. J.
,
Gopinathan
,
A.
,
McIntyre
,
D.
,
Honess
,
D.
,
Davidson
,
C. J.
,
Gopinathan
,
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.
,
Whitebrea
,
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
.
40.
Spring
,
B. Q.
,
Sears
,
R. B.
,
Zheng
,
L. Z.
,
Mai
,
Z.
,
Watanabe
,
R.
,
Sherwood
,
M. E.
,
Schoenfeld
,
D. A.
,
Pogue
,
B. W.
,
Pereira
,
S. P.
,
Villa
,
E.
, and
Hasan
,
T.
,
2016
, “
A Photoactivable Multi-Inhibitor Nanoliposome for Tumour Control and Simultaneous Inhibition of Treatment Escape Pathways
,”
Nat. Nanotechnol.
,
11
(
4
), pp.
378
387
.
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