Transforming growth factor-β limits secretion of lumican by activated stellate cells within primary pancreatic adenocarcinoma tumors

Ya'An Kang, David Roife, Yeonju Lee, Hailong Lv, Rei Suzuki, Jianhua Ling, Mayrim V. Rios Perez, Xinqun Li, Bingbing Dai, Michael Pratt, Mark Truty, Deyali Chatterjee, Huamin Wang, Ryan M. Thomas, Yu Wang, Eugene J. Koay, Paul J. Chiao, Matthew H. Katz, Jason B. Fleming

Research output: Contribution to journalArticle

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Abstract

Purpose: Pancreatic ductal adenocarcinoma (PDAC) is lethal cancer whose primary tumor is characterized by dense composition of cancer cells, stromal cells, and extracellular matrix (ECM) composed largely of collagen. Within the PDAC tumor microenvironment, activated pancreatic stellate cells (PSC) are the dominant stromal cell type and responsible for collagen deposition. Lumican is a secreted proteoglycan that regulates collagen fibril assembly. We have previously identified that the presence of lumican in the ECM surrounding PDAC cells is associated with improved patient outcome after multimodal therapy and surgical removal of localized PDAC. Experimental Design: Lumican expression in PDAC from 27 patients was determined by IHC and quantitatively analyzed for colocalization with PSCs. In vitro studies examined the molecular mechanisms of lumican transcription and secretion from PSCs (HPSCs and HPaSteC), and cell adhesion and migration assays examined the effect of lumican on PSCs in a collagen-rich environment. Results: Here we identify PSCs as a significant source of extracellular lumican production through quantitative IHC analysis. We demonstrate that the cytokine, TGF-β, negatively regulates lumican gene transcription within HPSCs through its canonical signaling pathway and binding of SMAD4 to novel SBEs identified within the promoter region. In addition, we found that the ability of HPSCs to produce and secrete extracellular lumican significantly enhances HPSCs adhesion and mobility on collagen. Conclusions: Our results demonstrate that activated pancreatic stellate cells within PDAC secrete lumican under the negative control of TGF-β once secreted, the extracellular lumican enhances stellate cell adhesion and mobility in a collagen-rich environment. Clin Cancer Res; 22(19); 4934-46.

Original languageEnglish (US)
Pages (from-to)4934-4946
Number of pages13
JournalClinical Cancer Research
Volume22
Issue number19
DOIs
StatePublished - Oct 1 2016

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Transforming Growth Factors
Adenocarcinoma
Collagen
Neoplasms
Pancreatic Stellate Cells
Stromal Cells
Cell Adhesion
Extracellular Matrix
Cell Migration Assays
Lumican
Tumor Microenvironment
Proteoglycans
Genetic Promoter Regions
Research Design
Cytokines

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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Transforming growth factor-β limits secretion of lumican by activated stellate cells within primary pancreatic adenocarcinoma tumors. / Kang, Ya'An; Roife, David; Lee, Yeonju; Lv, Hailong; Suzuki, Rei; Ling, Jianhua; Rios Perez, Mayrim V.; Li, Xinqun; Dai, Bingbing; Pratt, Michael; Truty, Mark; Chatterjee, Deyali; Wang, Huamin; Thomas, Ryan M.; Wang, Yu; Koay, Eugene J.; Chiao, Paul J.; Katz, Matthew H.; Fleming, Jason B.

In: Clinical Cancer Research, Vol. 22, No. 19, 01.10.2016, p. 4934-4946.

Research output: Contribution to journalArticle

Kang, YA, Roife, D, Lee, Y, Lv, H, Suzuki, R, Ling, J, Rios Perez, MV, Li, X, Dai, B, Pratt, M, Truty, M, Chatterjee, D, Wang, H, Thomas, RM, Wang, Y, Koay, EJ, Chiao, PJ, Katz, MH & Fleming, JB 2016, 'Transforming growth factor-β limits secretion of lumican by activated stellate cells within primary pancreatic adenocarcinoma tumors', Clinical Cancer Research, vol. 22, no. 19, pp. 4934-4946. https://doi.org/10.1158/1078-0432.CCR-15-2780
Kang, Ya'An ; Roife, David ; Lee, Yeonju ; Lv, Hailong ; Suzuki, Rei ; Ling, Jianhua ; Rios Perez, Mayrim V. ; Li, Xinqun ; Dai, Bingbing ; Pratt, Michael ; Truty, Mark ; Chatterjee, Deyali ; Wang, Huamin ; Thomas, Ryan M. ; Wang, Yu ; Koay, Eugene J. ; Chiao, Paul J. ; Katz, Matthew H. ; Fleming, Jason B. / Transforming growth factor-β limits secretion of lumican by activated stellate cells within primary pancreatic adenocarcinoma tumors. In: Clinical Cancer Research. 2016 ; Vol. 22, No. 19. pp. 4934-4946.
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author = "Ya'An Kang and David Roife and Yeonju Lee and Hailong Lv and Rei Suzuki and Jianhua Ling and {Rios Perez}, {Mayrim V.} and Xinqun Li and Bingbing Dai and Michael Pratt and Mark Truty and Deyali Chatterjee and Huamin Wang and Thomas, {Ryan M.} and Yu Wang and Koay, {Eugene J.} and Chiao, {Paul J.} and Katz, {Matthew H.} and Fleming, {Jason B.}",
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T1 - Transforming growth factor-β limits secretion of lumican by activated stellate cells within primary pancreatic adenocarcinoma tumors

AU - Kang, Ya'An

AU - Roife, David

AU - Lee, Yeonju

AU - Lv, Hailong

AU - Suzuki, Rei

AU - Ling, Jianhua

AU - Rios Perez, Mayrim V.

AU - Li, Xinqun

AU - Dai, Bingbing

AU - Pratt, Michael

AU - Truty, Mark

AU - Chatterjee, Deyali

AU - Wang, Huamin

AU - Thomas, Ryan M.

AU - Wang, Yu

AU - Koay, Eugene J.

AU - Chiao, Paul J.

AU - Katz, Matthew H.

AU - Fleming, Jason B.

PY - 2016/10/1

Y1 - 2016/10/1

N2 - Purpose: Pancreatic ductal adenocarcinoma (PDAC) is lethal cancer whose primary tumor is characterized by dense composition of cancer cells, stromal cells, and extracellular matrix (ECM) composed largely of collagen. Within the PDAC tumor microenvironment, activated pancreatic stellate cells (PSC) are the dominant stromal cell type and responsible for collagen deposition. Lumican is a secreted proteoglycan that regulates collagen fibril assembly. We have previously identified that the presence of lumican in the ECM surrounding PDAC cells is associated with improved patient outcome after multimodal therapy and surgical removal of localized PDAC. Experimental Design: Lumican expression in PDAC from 27 patients was determined by IHC and quantitatively analyzed for colocalization with PSCs. In vitro studies examined the molecular mechanisms of lumican transcription and secretion from PSCs (HPSCs and HPaSteC), and cell adhesion and migration assays examined the effect of lumican on PSCs in a collagen-rich environment. Results: Here we identify PSCs as a significant source of extracellular lumican production through quantitative IHC analysis. We demonstrate that the cytokine, TGF-β, negatively regulates lumican gene transcription within HPSCs through its canonical signaling pathway and binding of SMAD4 to novel SBEs identified within the promoter region. In addition, we found that the ability of HPSCs to produce and secrete extracellular lumican significantly enhances HPSCs adhesion and mobility on collagen. Conclusions: Our results demonstrate that activated pancreatic stellate cells within PDAC secrete lumican under the negative control of TGF-β once secreted, the extracellular lumican enhances stellate cell adhesion and mobility in a collagen-rich environment. Clin Cancer Res; 22(19); 4934-46.

AB - Purpose: Pancreatic ductal adenocarcinoma (PDAC) is lethal cancer whose primary tumor is characterized by dense composition of cancer cells, stromal cells, and extracellular matrix (ECM) composed largely of collagen. Within the PDAC tumor microenvironment, activated pancreatic stellate cells (PSC) are the dominant stromal cell type and responsible for collagen deposition. Lumican is a secreted proteoglycan that regulates collagen fibril assembly. We have previously identified that the presence of lumican in the ECM surrounding PDAC cells is associated with improved patient outcome after multimodal therapy and surgical removal of localized PDAC. Experimental Design: Lumican expression in PDAC from 27 patients was determined by IHC and quantitatively analyzed for colocalization with PSCs. In vitro studies examined the molecular mechanisms of lumican transcription and secretion from PSCs (HPSCs and HPaSteC), and cell adhesion and migration assays examined the effect of lumican on PSCs in a collagen-rich environment. Results: Here we identify PSCs as a significant source of extracellular lumican production through quantitative IHC analysis. We demonstrate that the cytokine, TGF-β, negatively regulates lumican gene transcription within HPSCs through its canonical signaling pathway and binding of SMAD4 to novel SBEs identified within the promoter region. In addition, we found that the ability of HPSCs to produce and secrete extracellular lumican significantly enhances HPSCs adhesion and mobility on collagen. Conclusions: Our results demonstrate that activated pancreatic stellate cells within PDAC secrete lumican under the negative control of TGF-β once secreted, the extracellular lumican enhances stellate cell adhesion and mobility in a collagen-rich environment. Clin Cancer Res; 22(19); 4934-46.

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