Pancreatic stellate cells: partners in crime with pancreatic cancer cells.

Pancreatic stellate cells (PSC) produce the stromal reaction in pancreatic cancer, but their role in cancer progression is not fully elucidated. We examined the influence of PSCs on pancreatic cancer growth using (a) an orthotopic model of pancreatic cancer and (b) cultured human PSCs (hPSC) and human pancreatic cancer cell lines MiaPaCa-2 and Panc-1. Athymic mice received an intrapancreatic injection of saline, hPSCs, MiaPaCa-2 cells, or hPSCs + MiaPaCa-2. After 7 weeks, tumor size, metastases, and tumor histology were assessed. In vitro studies assessed the effect of cancer cell secretions on PSC migration and the effect of hPSC secretions on cancer cell proliferation, apoptosis, and migration. Possible mediators of the effects of hPSC secretions on cancer cell proliferation were examined using neutralizing antibodies. Compared with mice receiving MiaPaCa-2 cells alone, mice injected with hPSCs + MiaPaCa-2 exhibited (a) increased tumor size and regional and distant metastasis, (b) fibrotic bands (desmoplasia) containing activated PSCs within tumors, and (c) increased tumor cell numbers. In vitro studies showed that, in the presence of pancreatic cancer cells, PSC migration was significantly increased. Furthermore, hPSC secretions induced the proliferation and migration, but inhibited the apoptosis, of MiaPaCa-2 and Panc-1 cells. The proliferative effect of hPSC secretions on pancreatic cancer cells was inhibited in the presence of neutralizing antibody to platelet-derived growth factor. Our studies indicate a significant interaction between pancreatic cancer cells and stromal cells (PSCs) and imply that pancreatic cancer cells recruit stromal cells to establish an environment that promotes cancer progression.

[1]  M. Korsten,et al.  Pancreatic stellate cells respond to inflammatory cytokines: potential role in chronic pancreatitis , 2002, Gut.

[2]  M. Tempero,et al.  Pancreatic cancer. , 1998, Current opinion in oncology.

[3]  G. W. Snedecor.  Statistical Methods , 1964 .

[4]  A. Buck,et al.  Pancreatic carcinoma cells induce fibrosis by stimulating proliferation and matrix synthesis of stellate cells. , 2005, Gastroenterology.

[5]  M. Bissell,et al.  The origin of the myofibroblasts in breast cancer. Recapitulation of tumor environment in culture unravels diversity and implicates converted fibroblasts and recruited smooth muscle cells. , 1995, The Journal of clinical investigation.

[6]  M. J. Lee.  Epidemiology and Risk Factors in Pancreatic Cancer. , 2004 .

[7]  S. Ashley,et al.  CEACAM6 gene silencing impairs anoikis resistance and in vivo metastatic ability of pancreatic adenocarcinoma cells , 2004, Oncogene.

[8]  V. Go.  The Pancreas : biology, pathobiology, and disease , 1993 .

[9]  M. Korsten,et al.  Pancreatic stellate cells are activated by proinflammatory cytokines: implications for pancreatic fibrogenesis , 1999, Gut.

[10]  P. Pederzoli,et al.  Collagen type I synthesized by pancreatic periacinar stellate cells (PSC) co‐localizes with lipid peroxidation‐derived aldehydes in chronic alcoholic pancreatitis , 2000, The Journal of pathology.

[11]  H. Friess,et al.  Pancreatic cancer: the potential clinical relevance of alterations in growth factors and their receptors , 2004, Journal of Molecular Medicine.

[12]  J. Cusack,et al.  Heparin-binding EGF-like growth factor is an early response gene to chemotherapy and contributes to chemotherapy resistance , 2007, Oncogene.

[13]  R. Schmid,et al.  Identification, culture, and characterization of pancreatic stellate cells in rats and humans. , 1998, Gastroenterology.

[14]  D. Ryan,et al.  Pancreatic Cancer: Local Success and Distant Failure. , 1998, The oncologist.

[15]  J S Wilson,et al.  Cell migration: a novel aspect of pancreatic stellate cell biology , 2003, Gut.

[16]  J. Ringel,et al.  Transforming Growth Factor-β1 Induces Desmoplasia in an Experimental Model of Human Pancreatic Carcinoma , 2001 .

[17]  D. C. Sheehan,et al.  Theory and Practice of Histotechnology , 1980 .

[18]  J. Iredale,et al.  Expression of transforming growth factor-beta 1 by pancreatic stellate cells and its implications for matrix secretion and turnover in chronic pancreatitis. , 2002, The American journal of pathology.

[19]  D. Nowak,et al.  Novel agents aiming at specific molecular targets increase chemosensitivity and overcome chemoresistance in hematopoietic malignancies. , 2006, Current pharmaceutical design.

[20]  John A. Kiernan,et al.  Histological and Histochemical Methods: Theory and Practice , 1981 .

[21]  I. Fidler,et al.  In vivo selection and characterization of metastatic variants from human pancreatic adenocarcinoma by using orthotopic implantation in nude mice. , 1999, Neoplasia.

[22]  M. Korsten,et al.  Periacinar stellate shaped cells in rat pancreas: identification, isolation, and culture , 1998, Gut.

[23]  Ahlgren Jd.  Epidemiology and risk factors in pancreatic cancer , 1996 .

[24]  M. Korsten,et al.  Does alcohol directly stimulate pancreatic fibrogenesis? Studies with rat pancreatic stellate cells. , 2000, Gastroenterology.

[25]  P. Hein,et al.  Carcinoma-associated fibroblasts stimulate tumor progression of initiated human epithelium , 2000, Breast Cancer Research.

[26]  D. Goldstein,et al.  Cancer Cells Pancreatic Stellate Cells : Partners in Crime with Pancreatic , 2008 .

[27]  M. Korsten,et al.  Rat pancreatic stellate cells secrete matrix metalloproteinases: implications for extracellular matrix turnover , 2003, Gut.

[28]  Rakesh K. Kumar,et al.  Pancreatic stellate cell migration: role of the phosphatidylinositol 3-kinase(PI3-kinase) pathway. , 2004, Biochemical pharmacology.

[29]  H. Friess,et al.  Enhanced expression of TGF-betas and their receptors in human acute pancreatitis. , 1998, Annals of surgery.

[30]  M J Bissell,et al.  Cellular changes involved in conversion of normal to malignant breast: importance of the stromal reaction. , 1996, Physiological reviews.

[31]  R. Schmid,et al.  Identification of mediators stimulating proliferation and matrix synthesis of rat pancreatic stellate cells. , 2001, American journal of physiology. Cell physiology.

[32]  Jinshun Zhao,et al.  Sensitivity and specificity of different staining methods to monitor apoptosis induced by oxidative stress in adherent cells. , 2003, Chinese medical journal.

[33]  S. Pandol,et al.  Extracellular matrix proteins protect pancreatic cancer cells from death via mitochondrial and nonmitochondrial pathways. , 2003, Gastroenterology.

[34]  Y. Wong,et al.  Growth factors and epithelial-stromal interactions in prostate cancer development. , 2000, International review of cytology.

[35]  A. Jemal,et al.  Cancer Statistics, 2006 , 2006, CA: a cancer journal for clinicians.

[36]  H. Yamamoto,et al.  Advanced glycation endproducts-receptor interactions stimulate the growth of human pancreatic cancer cells through the induction of platelet-derived growth factor-B. , 1996, Biochemical and biophysical research communications.

[37]  J. Braganza.  The Pancreas: Biology, Pathobiology and Disease , 1994 .

[38]  J S Wilson,et al.  Activation of pancreatic stellate cells in human and experimental pancreatic fibrosis. , 1999, The American journal of pathology.

[39]  J S Wilson,et al.  Desmoplastic Reaction in Pancreatic Cancer: Role of Pancreatic Stellate Cells , 2004, Pancreas.

[40]  R. Bell,et al.  Myofibroblasts are responsible for the desmoplastic reaction surrounding human pancreatic carcinomas. , 2002, Surgery.

[41]  M. Korc,et al.  Differential binding and biological activities of epidermal growth factor and transforming growth factor alpha in a human pancreatic cancer cell line. , 1991, Cancer research.

[42]  M. Korsten,et al.  The effect of ethanol on pancreatic enzymes--a dietary artefact? , 1998, Biochimica et biophysica acta.