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The tyrosine kinase inhibitor imatinib augments extracellular fluid exchange and reduces average collagen fibril diameter in experimental carcinoma

Olsson, Olof LU ; Gustafsson, Renata LU ; In 'T Zandt, René LU ; Friman, Tomas; Maccarana, Marco LU ; Tykesson, Emil LU ; Oldberg, Åke LU ; Rubin, Kristofer LU and Kalamajski, Sebastian LU (2016) In Molecular Cancer Therapeutics 15(10). p.2455-2464
Abstract

A typical obstacle to cancer therapy is the limited distribution of low molecular weight anticancer drugs within the carcinoma tissue. In experimental carcinoma, imatinib (STI571) increases efficacy of synchronized chemotherapy, reduces tumor interstitial fluid pressure, and increases interstitial fluid volume. STI571 also increases the water-perfusable fraction in metastases from human colorectal adenocarcinomas. Because the mechanism(s) behind these effects have not been fully elucidated, we investigated the hypothesis that STI571 alters specific properties of the stromal extracellular matrix. We analyzed STI571-treated human colorectal KAT-4/HT-29 experimental carcinomas, known to have a welldeveloped stromal compartment, for solute... (More)

A typical obstacle to cancer therapy is the limited distribution of low molecular weight anticancer drugs within the carcinoma tissue. In experimental carcinoma, imatinib (STI571) increases efficacy of synchronized chemotherapy, reduces tumor interstitial fluid pressure, and increases interstitial fluid volume. STI571 also increases the water-perfusable fraction in metastases from human colorectal adenocarcinomas. Because the mechanism(s) behind these effects have not been fully elucidated, we investigated the hypothesis that STI571 alters specific properties of the stromal extracellular matrix. We analyzed STI571-treated human colorectal KAT-4/HT-29 experimental carcinomas, known to have a welldeveloped stromal compartment, for solute exchange and glycosaminoglycan content, as well as collagen content, structure, and synthesis. MRI of STI571-treated KAT-4/HT-29 experimental carcinomas showed a significantly increased efficacy in dynamic exchanges of solutes between tumor interstitium and blood. This effect was paralleled by a distinct change of the stromal collagen network architecture, manifested by a decreased average collagen fibril diameter, and increased collagen turnover. The glycosaminoglycan content was unchanged. Furthermore, the apparent effects on the stromal cellular composition were limited to a reduction in an NG2-positive stromal cell population. The current data support the hypothesis that the collagen network architecture influences the dynamic exchanges of solutes between blood and carcinoma tissue. It is conceivable that STI571 reprograms distinct nonvascular stromal cells to produce a looser extracellular matrix, ultimately improving transport characteristics for traditional chemotherapeutic agents.

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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Molecular Cancer Therapeutics
volume
15
issue
10
pages
10 pages
publisher
American Association for Cancer Research
external identifiers
  • scopus:84990946957
  • wos:000385636300018
ISSN
1535-7163
DOI
10.1158/1535-7163.MCT-16-0026
language
English
LU publication?
yes
id
959f343a-cfc5-4a33-a789-ee91a4a59db2
date added to LUP
2016-11-01 12:45:19
date last changed
2017-09-24 05:02:33
@article{959f343a-cfc5-4a33-a789-ee91a4a59db2,
  abstract     = {<p>A typical obstacle to cancer therapy is the limited distribution of low molecular weight anticancer drugs within the carcinoma tissue. In experimental carcinoma, imatinib (STI571) increases efficacy of synchronized chemotherapy, reduces tumor interstitial fluid pressure, and increases interstitial fluid volume. STI571 also increases the water-perfusable fraction in metastases from human colorectal adenocarcinomas. Because the mechanism(s) behind these effects have not been fully elucidated, we investigated the hypothesis that STI571 alters specific properties of the stromal extracellular matrix. We analyzed STI571-treated human colorectal KAT-4/HT-29 experimental carcinomas, known to have a welldeveloped stromal compartment, for solute exchange and glycosaminoglycan content, as well as collagen content, structure, and synthesis. MRI of STI571-treated KAT-4/HT-29 experimental carcinomas showed a significantly increased efficacy in dynamic exchanges of solutes between tumor interstitium and blood. This effect was paralleled by a distinct change of the stromal collagen network architecture, manifested by a decreased average collagen fibril diameter, and increased collagen turnover. The glycosaminoglycan content was unchanged. Furthermore, the apparent effects on the stromal cellular composition were limited to a reduction in an NG2-positive stromal cell population. The current data support the hypothesis that the collagen network architecture influences the dynamic exchanges of solutes between blood and carcinoma tissue. It is conceivable that STI571 reprograms distinct nonvascular stromal cells to produce a looser extracellular matrix, ultimately improving transport characteristics for traditional chemotherapeutic agents.</p>},
  author       = {Olsson, Olof and Gustafsson, Renata and In 'T Zandt, René and Friman, Tomas and Maccarana, Marco and Tykesson, Emil and Oldberg, Åke and Rubin, Kristofer and Kalamajski, Sebastian},
  issn         = {1535-7163},
  language     = {eng},
  month        = {10},
  number       = {10},
  pages        = {2455--2464},
  publisher    = {American Association for Cancer Research},
  series       = {Molecular Cancer Therapeutics},
  title        = {The tyrosine kinase inhibitor imatinib augments extracellular fluid exchange and reduces average collagen fibril diameter in experimental carcinoma},
  url          = {http://dx.doi.org/10.1158/1535-7163.MCT-16-0026},
  volume       = {15},
  year         = {2016},
}