start-ver=1.4
cd-journal=joma
no-vol=230
cd-vols=
no-issue=
article-no=
start-page=109
end-page=115
dt-received=
dt-revised=
dt-accepted=
dt-pub-year=2016
dt-pub=20160528
dt-online=
en-article=
kn-article=
en-subject=
kn-subject=
en-title=
kn-title=Increased fibrosis and impaired intratumoral accumulation of macromolecules in a murine model of pancreatic cancer co-administered with FGF-2
en-subtitle=
kn-subtitle=
en-abstract=
kn-abstract=Pancreatic cancer is notorious for its poor prognosis. The histopathologic characteristic of pancreatic ductal adenocarcinoma (PDAC), which is the most common type of pancreatic cancer, is fibrosis within tumor tissue. Although fibrosis within tumor tissue is thought to impede drug therapy by interfering with the intratumoral accumulation of anti-tumor drugs, this hypothesis has yet to be proven directly in preclinical models. Here, we evaluated the effect of enhanced fibrosis on intratumoral accumulation of macromolecular drugs by increasing fibrosis in a murine tumor model of subcutaneously xenografted BxPC-3, a human PDAC cell line. When fibroblast growth factor-2 (FGF-2) was co-administered upon BxPC-3 inoculation, stromal fibrotic area was increased and was characterized by augmented murine collagen accumulation compared to inoculation of BxPC-3 alone, which correlated with increased monocyte/macrophage contents in the tumor tissues. We further discovered that the intratumoral accumulation of intravenously administrated fluorescein isothiocyanate-dextran of 2,000,000 Da (2 MDa) was significantly reduced in the FGF-2 co-administered tumors despite unaltered hyaluronan accumulation and pericyte coverage of the tumor neovasculature and increased lymphangiogenesis. Finally, we found that FGF-2 co-administered tumors are more refractory to macromolecular drug therapy using nab-paclitaxel (Abraxane). The model established and analyzed in this study, characterized by increased fibrotic component, provides a preclinical animal model suited to predict the intratumoral accumulation of macromolecular drugs and to evaluate the efficacy of drugs targeting the tumor stroma.
en-copyright=
kn-copyright=

en-aut-name=SakaiSatoshi
en-aut-sei=Sakai
en-aut-mei=Satoshi
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=1
ORCID=

en-aut-name=IwataCaname
en-aut-sei=Iwata
en-aut-mei=Caname
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=2
ORCID=

en-aut-name=TanakaHiroyoshi Y.
en-aut-sei=Tanaka
en-aut-mei=Hiroyoshi Y.
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=3
ORCID=

en-aut-name=CabralHoracio
en-aut-sei=Cabral
en-aut-mei=Horacio
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=4
ORCID=

en-aut-name=MorishitaYasuyuki
en-aut-sei=Morishita
en-aut-mei=Yasuyuki
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=5
ORCID=

en-aut-name=MiyazonKohei
en-aut-sei=Miyazon
en-aut-mei=Kohei
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=6
ORCID=

en-aut-name=KanoMitsunobu R.
en-aut-sei=Kano
en-aut-mei=Mitsunobu R.
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=7
ORCID=

affil-num=1
en-affil=Graduate School of Medicine, The University of Tokyo
kn-affil=

affil-num=2
en-affil=Graduate School of Medicine, The University of Tokyo
kn-affil=

affil-num=3
en-affil= Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University
kn-affil=

affil-num=4
en-affil=Graduate School of Engineering, The University of Tokyo
kn-affil=

affil-num=5
en-affil=Graduate School of Medicine, The University of Tokyo
kn-affil=

affil-num=6
en-affil=Graduate School of Medicine, The University of Tokyo
kn-affil=

affil-num=7
en-affil=Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University
kn-affil=
en-keyword=Macromolecular drugs
kn-keyword=Macromolecular drugs
en-keyword=Drug distribution
kn-keyword=Drug distribution
en-keyword=Pancreatic ductal adenocarcinoma
kn-keyword=Pancreatic ductal adenocarcinoma
en-keyword=Fibrosis
kn-keyword=Fibrosis
en-keyword=FGF-2
kn-keyword=FGF-2
END