Hedgehog signaling between cancer cells and hepatic stellate cells in promoting cholangiocarcinoma

Younjoo Kim, Myeong Ok Kim, Jin Sun Shin, Sun Hoo Park, Sang Bum Kim, Jin Kim, Su Cheol Park, Chul Ju Han, Ji Kon Ryu, Yong Bum Yoon, Young-Tae Kim

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Background. Aberrant Hedgehog (HH) signaling activation is important in cancer growth and mediates the interaction between cancer cells and the surrounding stromal cells. This study investigated the role of HH signaling on the growth of cholangiocarcinoma (CC), focusing on the interaction of CC cells with stromal cells. Methods. To evaluate the interaction between human CC cells (SNU-1196, SNU-246, SNU-308, SNU-1079, and HuCCT-1) and stromal cells (hepatic stellate cell line, Lx-2), co-culture proliferation, migration, and invasion assays were performed. In vivo nude mice experiments were conducted using two groups-HuCCT-1 single implant xenograft (SX) and co-implant xenograft (CX) with HuCCT-1 and Lx-2. Results. When HuCCT-1 cells were co-cultured with Lx-2 cells, the expression of HH signaling-related proteins increased in both HuCCT-1 and Lx-2 cells. Co-culture with Lx-2 cells stimulated the proliferation, migration, and invasion of CC cells, and these effects were mediated by HH signaling. Co-culture of HuCCT-1 and Lx-2 cells increased the secretion of several cytokines. In an ectopic xenograft model, Lx-2 co-implantation increased CC tumor growth and stimulated angiogenesis. Cyclopamine attenuated tumor growth in the CX group, but not in the HuCCT-1 mono-implant (SX) group. Cyclopamine treatment decreased CC cell proliferation, suppressed microvessel density, and increased tumor necrosis in the CX group, but not in the SX group. Conclusion. Hepatic stellate cells stimulate the proliferation, migration, and invasion of CC cells, promote angiogenesis through HH signaling activation, and render CC more susceptible to necrosis by HH inhibitor.

Original languageEnglish
Pages (from-to)2684-2698
Number of pages15
JournalAnnals of Surgical Oncology
Volume21
Issue number8
DOIs
StatePublished - 1 Jan 2014

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Hepatic Stellate Cells
Cholangiocarcinoma
Hedgehogs
Heterografts
Neoplasms
Stromal Cells
Coculture Techniques
Cell Proliferation
Growth
Necrosis
Microvessels
Nude Mice
Cell Communication
Cytokines
Cell Line

Cite this

Kim, Younjoo ; Kim, Myeong Ok ; Shin, Jin Sun ; Park, Sun Hoo ; Kim, Sang Bum ; Kim, Jin ; Park, Su Cheol ; Han, Chul Ju ; Ryu, Ji Kon ; Yoon, Yong Bum ; Kim, Young-Tae. / Hedgehog signaling between cancer cells and hepatic stellate cells in promoting cholangiocarcinoma. In: Annals of Surgical Oncology. 2014 ; Vol. 21, No. 8. pp. 2684-2698.
@article{269d896e666441459590b988cd366cf7,
title = "Hedgehog signaling between cancer cells and hepatic stellate cells in promoting cholangiocarcinoma",
abstract = "Background. Aberrant Hedgehog (HH) signaling activation is important in cancer growth and mediates the interaction between cancer cells and the surrounding stromal cells. This study investigated the role of HH signaling on the growth of cholangiocarcinoma (CC), focusing on the interaction of CC cells with stromal cells. Methods. To evaluate the interaction between human CC cells (SNU-1196, SNU-246, SNU-308, SNU-1079, and HuCCT-1) and stromal cells (hepatic stellate cell line, Lx-2), co-culture proliferation, migration, and invasion assays were performed. In vivo nude mice experiments were conducted using two groups-HuCCT-1 single implant xenograft (SX) and co-implant xenograft (CX) with HuCCT-1 and Lx-2. Results. When HuCCT-1 cells were co-cultured with Lx-2 cells, the expression of HH signaling-related proteins increased in both HuCCT-1 and Lx-2 cells. Co-culture with Lx-2 cells stimulated the proliferation, migration, and invasion of CC cells, and these effects were mediated by HH signaling. Co-culture of HuCCT-1 and Lx-2 cells increased the secretion of several cytokines. In an ectopic xenograft model, Lx-2 co-implantation increased CC tumor growth and stimulated angiogenesis. Cyclopamine attenuated tumor growth in the CX group, but not in the HuCCT-1 mono-implant (SX) group. Cyclopamine treatment decreased CC cell proliferation, suppressed microvessel density, and increased tumor necrosis in the CX group, but not in the SX group. Conclusion. Hepatic stellate cells stimulate the proliferation, migration, and invasion of CC cells, promote angiogenesis through HH signaling activation, and render CC more susceptible to necrosis by HH inhibitor.",
author = "Younjoo Kim and Kim, {Myeong Ok} and Shin, {Jin Sun} and Park, {Sun Hoo} and Kim, {Sang Bum} and Jin Kim and Park, {Su Cheol} and Han, {Chul Ju} and Ryu, {Ji Kon} and Yoon, {Yong Bum} and Young-Tae Kim",
year = "2014",
month = "1",
day = "1",
doi = "10.1245/s10434-014-3531-y",
language = "English",
volume = "21",
pages = "2684--2698",
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Kim, Y, Kim, MO, Shin, JS, Park, SH, Kim, SB, Kim, J, Park, SC, Han, CJ, Ryu, JK, Yoon, YB & Kim, Y-T 2014, 'Hedgehog signaling between cancer cells and hepatic stellate cells in promoting cholangiocarcinoma', Annals of Surgical Oncology, vol. 21, no. 8, pp. 2684-2698. https://doi.org/10.1245/s10434-014-3531-y

Hedgehog signaling between cancer cells and hepatic stellate cells in promoting cholangiocarcinoma. / Kim, Younjoo; Kim, Myeong Ok; Shin, Jin Sun; Park, Sun Hoo; Kim, Sang Bum; Kim, Jin; Park, Su Cheol; Han, Chul Ju; Ryu, Ji Kon; Yoon, Yong Bum; Kim, Young-Tae.

In: Annals of Surgical Oncology, Vol. 21, No. 8, 01.01.2014, p. 2684-2698.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Hedgehog signaling between cancer cells and hepatic stellate cells in promoting cholangiocarcinoma

AU - Kim, Younjoo

AU - Kim, Myeong Ok

AU - Shin, Jin Sun

AU - Park, Sun Hoo

AU - Kim, Sang Bum

AU - Kim, Jin

AU - Park, Su Cheol

AU - Han, Chul Ju

AU - Ryu, Ji Kon

AU - Yoon, Yong Bum

AU - Kim, Young-Tae

PY - 2014/1/1

Y1 - 2014/1/1

N2 - Background. Aberrant Hedgehog (HH) signaling activation is important in cancer growth and mediates the interaction between cancer cells and the surrounding stromal cells. This study investigated the role of HH signaling on the growth of cholangiocarcinoma (CC), focusing on the interaction of CC cells with stromal cells. Methods. To evaluate the interaction between human CC cells (SNU-1196, SNU-246, SNU-308, SNU-1079, and HuCCT-1) and stromal cells (hepatic stellate cell line, Lx-2), co-culture proliferation, migration, and invasion assays were performed. In vivo nude mice experiments were conducted using two groups-HuCCT-1 single implant xenograft (SX) and co-implant xenograft (CX) with HuCCT-1 and Lx-2. Results. When HuCCT-1 cells were co-cultured with Lx-2 cells, the expression of HH signaling-related proteins increased in both HuCCT-1 and Lx-2 cells. Co-culture with Lx-2 cells stimulated the proliferation, migration, and invasion of CC cells, and these effects were mediated by HH signaling. Co-culture of HuCCT-1 and Lx-2 cells increased the secretion of several cytokines. In an ectopic xenograft model, Lx-2 co-implantation increased CC tumor growth and stimulated angiogenesis. Cyclopamine attenuated tumor growth in the CX group, but not in the HuCCT-1 mono-implant (SX) group. Cyclopamine treatment decreased CC cell proliferation, suppressed microvessel density, and increased tumor necrosis in the CX group, but not in the SX group. Conclusion. Hepatic stellate cells stimulate the proliferation, migration, and invasion of CC cells, promote angiogenesis through HH signaling activation, and render CC more susceptible to necrosis by HH inhibitor.

AB - Background. Aberrant Hedgehog (HH) signaling activation is important in cancer growth and mediates the interaction between cancer cells and the surrounding stromal cells. This study investigated the role of HH signaling on the growth of cholangiocarcinoma (CC), focusing on the interaction of CC cells with stromal cells. Methods. To evaluate the interaction between human CC cells (SNU-1196, SNU-246, SNU-308, SNU-1079, and HuCCT-1) and stromal cells (hepatic stellate cell line, Lx-2), co-culture proliferation, migration, and invasion assays were performed. In vivo nude mice experiments were conducted using two groups-HuCCT-1 single implant xenograft (SX) and co-implant xenograft (CX) with HuCCT-1 and Lx-2. Results. When HuCCT-1 cells were co-cultured with Lx-2 cells, the expression of HH signaling-related proteins increased in both HuCCT-1 and Lx-2 cells. Co-culture with Lx-2 cells stimulated the proliferation, migration, and invasion of CC cells, and these effects were mediated by HH signaling. Co-culture of HuCCT-1 and Lx-2 cells increased the secretion of several cytokines. In an ectopic xenograft model, Lx-2 co-implantation increased CC tumor growth and stimulated angiogenesis. Cyclopamine attenuated tumor growth in the CX group, but not in the HuCCT-1 mono-implant (SX) group. Cyclopamine treatment decreased CC cell proliferation, suppressed microvessel density, and increased tumor necrosis in the CX group, but not in the SX group. Conclusion. Hepatic stellate cells stimulate the proliferation, migration, and invasion of CC cells, promote angiogenesis through HH signaling activation, and render CC more susceptible to necrosis by HH inhibitor.

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U2 - 10.1245/s10434-014-3531-y

DO - 10.1245/s10434-014-3531-y

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AN - SCOPUS:84905120618

VL - 21

SP - 2684

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JO - Annals of surgical oncology

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SN - 1068-9265

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