TY - JOUR
T1 - Three-dimensional modeling of the human fallopian tube fimbriae
AU - Eddie, Sharon L.
AU - Quartuccio, Suzanne M.
AU - Zhu, Jie
AU - Shepherd, Jessica A.
AU - Kothari, Rajul
AU - Kim, J. Julie
AU - Woodruff, Teresa K.
AU - Burdette, Joanna E.
N1 - Funding Information:
Generous funding for this work was provided by the American Cancer Society Illinois Division RSG-12-230-01-TBG and the NIH ( UH2TR000498-01 and UH3TR001207 ).
Publisher Copyright:
© 2015 Elsevier Inc. All rights reserved.
PY - 2015/2/1
Y1 - 2015/2/1
N2 - Objective. Ovarian cancer is the most lethal gynecological malignancy that affects women. Recent data suggests that the disease may originate in the fallopian fimbriae; however, the anatomical origin of ovarian carcinogenesis remains unclear. This is largely driven by our lack of knowledge regarding the structure and function of normal fimbriae and the relative paucity of models that accurately recapitulate the in vivo fallopian tube. Therefore, a human three-dimensional (3D) culture system was developed to examine the role of the fallopian fimbriae in serous tumorigenesis. Methods. Alginate matrix was utilized to support human fallopian fimbriae ex vivo. Fimbriae were cultured with factors hypothesized to contribute to carcinogenesis, namely; H2O2 (1 mM) a mimetic of oxidative stress, insulin (5 μg/ml) to stimulate glycolysis, and estradiol (E2, 10 nM) which peaks before ovulation. Cultures were evaluated for changes in proliferation and p53 expression, criteria utilized to identify potential precursor lesions. Further, secretory factors were assessed after treatment with E2 to identify if steroid signaling induces a pro-tumorigenic microenvironment. Results. 3D fimbriae cultures maintained normal tissue architecture up to 7 days, retaining both epithelial subtypes. Treatment of cultures with H2O2 or insulin significantly induced proliferation. However, p53 stabilization was unaffected by any particular treatment, although it was induced by ex vivo culturing. Moreover, E2-alone treatment significantly induced its canonical target PR and expression of IL8, a factor linked to poor outcome. Conclusions. 3D alginate cultures of human fallopian fimbriae provide an important microphysiological model, which can be further utilized to investigate serous tumorigenesis originating from the fallopian tube.
AB - Objective. Ovarian cancer is the most lethal gynecological malignancy that affects women. Recent data suggests that the disease may originate in the fallopian fimbriae; however, the anatomical origin of ovarian carcinogenesis remains unclear. This is largely driven by our lack of knowledge regarding the structure and function of normal fimbriae and the relative paucity of models that accurately recapitulate the in vivo fallopian tube. Therefore, a human three-dimensional (3D) culture system was developed to examine the role of the fallopian fimbriae in serous tumorigenesis. Methods. Alginate matrix was utilized to support human fallopian fimbriae ex vivo. Fimbriae were cultured with factors hypothesized to contribute to carcinogenesis, namely; H2O2 (1 mM) a mimetic of oxidative stress, insulin (5 μg/ml) to stimulate glycolysis, and estradiol (E2, 10 nM) which peaks before ovulation. Cultures were evaluated for changes in proliferation and p53 expression, criteria utilized to identify potential precursor lesions. Further, secretory factors were assessed after treatment with E2 to identify if steroid signaling induces a pro-tumorigenic microenvironment. Results. 3D fimbriae cultures maintained normal tissue architecture up to 7 days, retaining both epithelial subtypes. Treatment of cultures with H2O2 or insulin significantly induced proliferation. However, p53 stabilization was unaffected by any particular treatment, although it was induced by ex vivo culturing. Moreover, E2-alone treatment significantly induced its canonical target PR and expression of IL8, a factor linked to poor outcome. Conclusions. 3D alginate cultures of human fallopian fimbriae provide an important microphysiological model, which can be further utilized to investigate serous tumorigenesis originating from the fallopian tube.
KW - fallopian tube
KW - fimbriae
KW - microphysiological modeling
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U2 - 10.1016/j.ygyno.2014.12.015
DO - 10.1016/j.ygyno.2014.12.015
M3 - Article
C2 - 25527363
AN - SCOPUS:84923009459
SN - 0090-8258
VL - 136
SP - 348
EP - 354
JO - Gynecologic Oncology
JF - Gynecologic Oncology
IS - 2
ER -