Faculty Collaboration Database

Cancer-associated stromal fibroblasts promote pancreatic tumor progression. Cancer Res 2008 Feb 01;68(3):918-26

Date

02/05/2008

Pubmed ID

18245495

Pubmed Central ID

PMC2519173

DOI

10.1158/0008-5472.CAN-07-5714

Scopus ID

2-s2.0-38849141696 (requires institutional sign-in at Scopus site)   959 Citations

Abstract

Pancreatic adenocarcinoma is characterized by a dense background of tumor associated stroma originating from abundant pancreatic stellate cells. The aim of this study was to determine the effect of human pancreatic stellate cells (HPSC) on pancreatic tumor progression. HPSCs were isolated from resected pancreatic adenocarcinoma samples and immortalized with telomerase and SV40 large T antigen. Effects of HPSC conditioned medium (HPSC-CM) on in vitro proliferation, migration, invasion, soft-agar colony formation, and survival in the presence of gemcitabine or radiation therapy were measured in two pancreatic cancer cell lines. The effects of HPSCs on tumors were examined in an orthotopic murine model of pancreatic cancer by co-injecting them with cancer cells and analyzing growth and metastasis. HPSC-CM dose-dependently increased BxPC3 and Panc1 tumor cell proliferation, migration, invasion, and colony formation. Furthermore, gemcitabine and radiation therapy were less effective in tumor cells treated with HPSC-CM. HPSC-CM activated the mitogen-activated protein kinase and Akt pathways in tumor cells. Co-injection of tumor cells with HPSCs in an orthotopic model resulted in increased primary tumor incidence, size, and metastasis, which corresponded with the proportion of HPSCs. HPSCs produce soluble factors that stimulate signaling pathways related to proliferation and survival of pancreatic cancer cells, and the presence of HPSCs in tumors increases the growth and metastasis of these cells. These data indicate that stellate cells have an important role in supporting and promoting pancreatic cancer. Identification of HPSC-derived factors may lead to novel stroma-targeted therapies for pancreatic cancer.

Author List

Hwang RF, Moore T, Arumugam T, Ramachandran V, Amos KD, Rivera A, Ji B, Evans DB, Logsdon CD

Author

Douglas B. Evans MD Chair, Professor in the Surgery department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adenocarcinoma
Apoptosis
Cell Line, Tumor
Culture Media, Conditioned
Deoxycytidine
Disease Progression
Enzyme Activation
Fibroblasts
Humans
MAP Kinase Signaling System
Mitogen-Activated Protein Kinases
Neoplasm Metastasis
Pancreatic Neoplasms
Proto-Oncogene Proteins c-akt
Stromal Cells