Research Papers

Separation of Solid Stress From Interstitial Fluid Pressure in Pancreas Cancer Correlates With Collagen Area Fraction

[+] Author and Article Information
Michael D. Nieskoski, Kayla Marra, Jason R. Gunn, Stephen C. Kanick, B. Stuart Trembly

Thayer School of Engineering,
Dartmouth College,
Hanover, NH 03755

Marvin M. Doyley

Thayer School of Engineering,
Dartmouth College,
Hanover, NH 03755;
Department of Electrical and
Computer Engineering,
University of Rochester,
Rochester, NY 14627

Tayyaba Hasan

Wellman Center for Photomedicine,
Massachusetts General Hospital,
Harvard Medical School,
Boston, MA 02114

Stephen P. Pereira

Institute for Liver and Digestive Health,
University College London,
London NW3 2QG, UK

Brian W. Pogue

Thayer School of Engineering,
Dartmouth College,
Hanover, NH 03755
e-mail: Brian.W.Pogue@Dartmouth.edu

1Corresponding author.

Manuscript received October 17, 2016; final manuscript received March 3, 2017; published online April 18, 2017. Assoc. Editor: Jeffrey Ruberti.

J Biomech Eng 139(6), 061002 (Apr 18, 2017) (8 pages) Paper No: BIO-16-1409; doi: 10.1115/1.4036392 History: Received October 17, 2016; Revised March 03, 2017

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.

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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.
Freelove, R. , and Walling, A. , 2006, “ Pancreatic Cancer: Diagnosis and Management,” Am. Fam. Physician, 73(3), pp. 485–492. [PubMed]
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. [CrossRef] [PubMed]
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. [CrossRef] [PubMed]
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. [CrossRef] [PubMed]
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. [CrossRef] [PubMed]
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. [CrossRef] [PubMed]
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. [CrossRef] [PubMed]
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. [CrossRef] [PubMed]
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. [CrossRef] [PubMed]
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. [CrossRef] [PubMed]
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. [CrossRef] [PubMed]
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. [CrossRef]
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. [CrossRef] [PubMed]
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. [CrossRef]
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. [CrossRef] [PubMed]
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. [CrossRef] [PubMed]
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. [CrossRef] [PubMed]
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.
Ozerdem, U. , 2009, “ Measuring Interstitial Fluid Pressure With Fiberoptic Pressure Transducers,” Microvasc. Res., 77(2), pp. 226–229. [CrossRef] [PubMed]
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. [CrossRef] [PubMed]
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. [CrossRef] [PubMed]
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. [CrossRef] [PubMed]
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. [CrossRef] [PubMed]
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. [CrossRef] [PubMed]
Dolmans, D. , Fukumura, D. , and Jain, R. K. , 2003, “ Photodynamic Therapy for Cancer,” Nat. Rev. Cancer, 3(5), pp. 380–387. [CrossRef] [PubMed]
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. [CrossRef]
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. [CrossRef]
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. [CrossRef] [PubMed]
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. [CrossRef] [PubMed]
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.
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. [CrossRef] [PubMed]
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. [CrossRef] [PubMed]
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. [CrossRef]
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. [CrossRef] [PubMed]
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. [CrossRef] [PubMed]
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. [CrossRef] [PubMed]
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. [PubMed]
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. [CrossRef] [PubMed]
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. [CrossRef] [PubMed]


Grahic Jump Location
Fig. 1

Proposed description of the extracellular matrix component contributions that limit drug distribution in pancreatic cancer. The extracellular matrix component contributions that limit drug distribution and instigate widespread vascular collapse is outlined in (a). Excessive extracellular component deposition coupled with cellular proliferation results in growth-induced solid stress, causing reduced vascular and lymphatic patency and elevated interstitial fluid pressure, thereby, limiting convective transport of large macromolecules into the tumor interstitium (b).

Grahic Jump Location
Fig. 2

Novel technique for measuring individual pressure contributions in pancreatic cancer. A Millar Mikrotip pressure catheter (a) and a modified cover (b) were used to measure total tissue pressure (TTP) as a combination of solid stress (SS) and interstitial fluid pressure (IFP) (c) and IFP only (d). The modified attachment was designed to easily retract, thereby measurement of IFP and TTP were obtained without removing the probe from the tumor location, as illustrated in (e). In this tumor, the modified Millar presser sensor was placed in water from time = 0 to 2 min and placed in the tumor from time = 2 to 12 min. The modified cover was removed at time = 12 min and Millar pressure measurements (no PTFE cover) continued until time = 22 min.

Grahic Jump Location
Fig. 3

Correlation between collagen area fraction and total tissue pressure (TTP). Millar Mikrotip (SPR-671) pressure catheter was used to measure pressure in AsPC-1 tumors and this was compared to collagen area fraction analyzed ex vivo. A strong correlation was observed between collagen area fraction and TTP using a linear regression fit (R2 = 0.799; *p < 0.001). P-value was calculated under the null hypothesis no correlation between TTP and collagen. The y-intercept was 23 mmHg, approximately equal to microvascular pressure (MVP) found in literature [32]. Interstitial fluid pressure (IFP) will not exceed MVP indicating values of TTP > IFP represent solid stress (SS).Comparison between measured values of TTP (mean  = 48.8 mmHg) and IFP (mean = 12.8 mmHg) was made by a Welch t-test (**p < 0.001) for five tumors.

Grahic Jump Location
Fig. 4

Quantitative investigation on drug uptake in pancreatic tumors. Vascular structure and vascular patency were analyzed ex vivo with anti-CD31 immunostain (a) and DiOC7 stain (c), respectively. A statistically significant relationship existed between the orthotopic tumor location (12 tumors included) and subcutaneous tumor location (eight tumors included) for the anti-CD31 (b) stain (p < 0.05) but no apparent correlation with the DiOC7 stain (d); comparison was made by a Welch t-test. A statistically significant correlation between orthotopic location of verteporfin uptake and TTP (e) was determined using linear regression fit (R2 = 0.46, p < 0.04). P-value was computed under the null hypothesis of no correlation between fluorescence signal and TTP. A statistically significant relationship existed between the orthotopic tumor location (f) for verteporfin uptake compared with the subcutaneous tumor location was determined by a Welch t-test (p < 0.01). The p-values were computed against a null-hypothesis that no correlation exists. A zero-slope line indicated no correlation, as illustrated with the subcutaneous tumor location.



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