Cancer-associated stromal fibroblasts promote pancreatic tumor progression.
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.
Hwang
Rosa F
RF
Department of Surgical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77230-1402, USA. rhwang@mdanderson.org
Moore
Todd
T
Arumugam
Thiruvengadam
T
Ramachandran
Vijaya
V
Amos
Keith D
KD
Rivera
Armando
A
Ji
Baoan
B
Evans
Douglas B
DB
Logsdon
Craig D
CD
D000230:Adenocarcinoma / Q000473:pathology*; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D045744:Cell Line, Tumor; D017077:Culture Media, Conditioned; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D018450:Disease Progression; D004789:Enzyme Activation; D005347:Fibroblasts / Q000473:pathology*; D006801:Humans; D020935:MAP Kinase Signaling System; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009362:Neoplasm Metastasis; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000473:pathology* / Q000532:radiotherapy; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017154:Stromal Cells / Q000473:pathology; D000093542:Gemcitabine
D017077:Culture Media, Conditioned; D003841:Deoxycytidine; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases; D000093542:Gemcitabine