PMID- 22932871
OWN - NLM
STAT- MEDLINE
DCOM- 20121210
LR  - 20220321
IS  - 1091-6490 (Electronic)
IS  - 0027-8424 (Print)
IS  - 0027-8424 (Linking)
VI  - 109
IP  - 38
DP  - 2012 Sep 18
TI  - Causes, consequences, and remedies for growth-induced solid stress in murine and 
      human tumors.
PG  - 15101-8
AB  - The presence of growth-induced solid stresses in tumors has been suspected for 
      some time, but these stresses were largely estimated using mathematical models. 
      Solid stresses can deform the surrounding tissues and compress intratumoral 
      lymphatic and blood vessels. Compression of lymphatic vessels elevates 
      interstitial fluid pressure, whereas compression of blood vessels reduces blood 
      flow. Reduced blood flow, in turn, leads to hypoxia, which promotes tumor 
      progression, immunosuppression, inflammation, invasion, and metastasis and lowers 
      the efficacy of chemo-, radio-, and immunotherapies. Thus, strategies designed to 
      alleviate solid stress have the potential to improve cancer treatment. However, a 
      lack of methods for measuring solid stress has hindered the development of solid 
      stress-alleviating drugs. Here, we present a simple technique to estimate the 
      growth-induced solid stress accumulated within animal and human tumors, and we 
      show that this stress can be reduced by depleting cancer cells, fibroblasts, 
      collagen, and/or hyaluronan, resulting in improved tumor perfusion. Furthermore, 
      we show that therapeutic depletion of carcinoma-associated fibroblasts with an 
      inhibitor of the sonic hedgehog pathway reduces solid stress, decompresses blood 
      and lymphatic vessels, and increases perfusion. In addition to providing insights 
      into the mechanopathology of tumors, our approach can serve as a rapid screen for 
      stress-reducing and perfusion-enhancing drugs.
FAU - Stylianopoulos, Triantafyllos
AU  - Stylianopoulos T
AD  - Department of Radiation Oncology, Massachusetts General Hospital and Harvard 
      Medical School, Boston, MA 02114, USA.
FAU - Martin, John D
AU  - Martin JD
FAU - Chauhan, Vikash P
AU  - Chauhan VP
FAU - Jain, Saloni R
AU  - Jain SR
FAU - Diop-Frimpong, Benjamin
AU  - Diop-Frimpong B
FAU - Bardeesy, Nabeel
AU  - Bardeesy N
FAU - Smith, Barbara L
AU  - Smith BL
FAU - Ferrone, Cristina R
AU  - Ferrone CR
FAU - Hornicek, Francis J
AU  - Hornicek FJ
FAU - Boucher, Yves
AU  - Boucher Y
FAU - Munn, Lance L
AU  - Munn LL
FAU - Jain, Rakesh K
AU  - Jain RK
LA  - eng
GR  - R01 CA126642/CA/NCI NIH HHS/United States
GR  - P01 CA117969/CA/NCI NIH HHS/United States
GR  - P01 CA080124/CA/NCI NIH HHS/United States
GR  - R01CA126642/CA/NCI NIH HHS/United States
GR  - P01CA080124/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20120829
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 9004-61-9 (Hyaluronic Acid)
RN  - 9007-34-5 (Collagen)
SB  - IM
MH  - Adenocarcinoma/*pathology
MH  - Animals
MH  - Blood Vessels/pathology
MH  - Collagen/chemistry
MH  - Female
MH  - Fibroblasts/pathology
MH  - Humans
MH  - Hyaluronic Acid/chemistry
MH  - Hypoxia
MH  - Immunotherapy/methods
MH  - Mice
MH  - Mice, SCID
MH  - Models, Theoretical
MH  - Neoplasm Transplantation
MH  - Neoplasms/pathology
MH  - Pancreatic Ducts/*pathology
MH  - Pancreatic Neoplasms/*pathology
MH  - Stress, Mechanical
MH  - Stromal Cells/cytology
PMC - PMC3458380
COIS- Conflict of interest statement: R.K.J. received research grants from Dyax, 
      MedImmune, and Roche; received consultant fees from Dyax, Enlight, Noxxon, and 
      SynDevRx; owns equity in Enlight, SynDevRx, and XTuit; and serves on the Board of 
      Directors of XTuit and Board of Trustees of H&Q Healthcare Investors and H&Q Life 
      Sciences Investors. No reagents or funding from these companies were used in 
      these studies. Therefore, there is no significant financial or other competing 
      interest in the work.
EDAT- 2012/08/31 06:00
MHDA- 2012/12/12 06:00
PMCR- 2012/08/29
CRDT- 2012/08/31 06:00
PHST- 2012/08/31 06:00 [entrez]
PHST- 2012/08/31 06:00 [pubmed]
PHST- 2012/12/12 06:00 [medline]
PHST- 2012/08/29 00:00 [pmc-release]
AID - 1213353109 [pii]
AID - 201213353 [pii]
AID - 10.1073/pnas.1213353109 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 2012 Sep 18;109(38):15101-8. doi: 
      10.1073/pnas.1213353109. Epub 2012 Aug 29.