Cancer-Associated Stromal Fibroblasts Promote Pancreatic Tumor Progression
Rosa F. Hwang,Todd Moore,Thiruvengadam Arumugam,Vijaya Ramachandran,Keith D. Amos,Armando Rivera,Baoan Ji,Douglas B. Evans,Craig D. Logsdon +8 more
Reads0
Chats0
TLDR
Data indicate that stellate cells have an important role in supporting and promoting pancreatic cancer, and the presence of HPSCs in tumors increases the growth and metastasis of these cells.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.read more
Citations
More filters
Journal ArticleDOI
Stromal elements act to restrain, rather than support, pancreatic ductal adenocarcinoma
Andrew D. Rhim,Andrew D. Rhim,Paul E. Oberstein,Dafydd H. Thomas,Emily T. Mirek,Carmine F. Palermo,Stephen A. Sastra,Erin N. Dekleva,Tyler Saunders,Claudia P. Becerra,Ian W. Tattersall,C. Benedikt Westphalen,Jan Kitajewski,Maite G. Fernandez-Barrena,Martin E. Fernandez-Zapico,Christine A. Iacobuzio-Donahue,Kenneth P. Olive,Ben Z. Stanger +17 more
TL;DR: De deleting Shh in a well-defined mouse model of PDAC demonstrated that some components of the tumor stroma can act to restrain tumor growth, and administration of VEGFR blocking antibody selectively improved survival of Shh-deficient tumors.
Journal ArticleDOI
Distinct populations of inflammatory fibroblasts and myofibroblasts in pancreatic cancer
Daniel Öhlund,Daniel Öhlund,Daniel Öhlund,Abram Handly-Santana,Abram Handly-Santana,Giulia Biffi,Giulia Biffi,Ela Elyada,Ela Elyada,Ana S. Almeida,Ana S. Almeida,Mariano Ponz-Sarvise,Mariano Ponz-Sarvise,Mariano Ponz-Sarvise,Vincenzo Corbo,Tobiloba E. Oni,Tobiloba E. Oni,Tobiloba E. Oni,Stephen Hearn,Eun Jung Lee,Eun Jung Lee,Iok In Christine Chio,Iok In Christine Chio,Chang-Il Hwang,Chang-Il Hwang,Hervé Tiriac,Hervé Tiriac,Lindsey A. Baker,Lindsey A. Baker,Dannielle D. Engle,Dannielle D. Engle,Christine Feig,Anne Kultti,Mikala Egeblad,Douglas T. Fearon,James M. Crawford,Hans Clevers,Young-Kyu Park,Young-Kyu Park,David A. Tuveson,David A. Tuveson +40 more
TL;DR: Direct evidence for CAF heterogeneity in PDA tumor biology is provided, providing direct evidence for disease etiology and therapeutic development in mouse and human PDA tissue.
Journal ArticleDOI
Virtual microdissection identifies distinct tumor- and stroma-specific subtypes of pancreatic ductal adenocarcinoma
Richard A. Moffitt,Raoud Marayati,Elizabeth L. Flate,Keith E. Volmar,S. Gabriela Herrera Loeza,Katherine A. Hoadley,Naim U. Rashid,Lindsay A. Williams,Samuel C. Eaton,Alexander H. Chung,Jadwiga K. Smyla,Judy M. Anderson,Hong Jin Kim,David J. Bentrem,Mark S. Talamonti,Christine A. Iacobuzio-Donahue,Michael A. Hollingsworth,Jen Jen Yeh +17 more
TL;DR: By digitally separating tumor, stromal and normal gene expression, two tumor subtypes are identified and validated, including a 'basal-like' subtype that has worse outcome and is molecularly similar to basal tumors in bladder and breast cancers.
Journal ArticleDOI
The Pancreas Cancer Microenvironment
Christine Feig,Aarthi Gopinathan,Albrecht Neesse,Derek S. Chan,Natalie Cook,David A. Tuveson +5 more
TL;DR: The current understanding of the PDA tumor microenvironment is reviewed, opportunities for further exploration that may benefit patients are highlighted, and methods that alter stromal composition or function are under active investigation.
References
More filters
Book
Cancer : Principles and Practice of Oncology
TL;DR: Part I: Molecular Biology of Cancer Molecular Methods in Oncology Section 1. Amplification Techniques Section 2. RNA Interference Section 3. cDNA arrays Section 4. Tissue arrays Section 5. Cytogenetics Section 6. Bioinformatics Genomics and Proteomics Molecular Targets in oncology.
Journal ArticleDOI
Fibroblasts in cancer
TL;DR: Fibroblasts are a key determinant in the malignant progression of cancer and represent an important target for cancer therapies.
Journal ArticleDOI
Identification of Pancreatic Cancer Stem Cells
Chenwei Li,David G. Heidt,Piero Dalerba,Charles F. Burant,Lanjing Zhang,Volkan Adsay,Max S. Wicha,Michael F. Clarke,Diane M. Simeone +8 more
TL;DR: This work identified a highly tumorigenic subpopulation of pancreatic cancer cells expressing the cell surface markers CD44, CD24, and epithelial-specific antigen (ESA) that showed the stem cell properties of self-renewal, the ability to produce differentiated progeny, and increased expression of the developmental signaling molecule sonic hedgehog.
Journal ArticleDOI
The microenvironment of the tumour-host interface
Lance A. Liotta,Elise C. Kohn +1 more
TL;DR: A new class of cancer therapies that targets this pathological communication interface between tumour cells and host cells is currently under development.
Journal ArticleDOI
A Perivascular Niche for Brain Tumor Stem Cells
Christopher Calabrese,Helen Poppleton,Mehmet Kocak,Twala L. Hogg,Christine E. Fuller,Blair Hamner,Eun Young Oh,M. Waleed Gaber,David Finklestein,Meredith Allen,Adrian J. Frank,Ildar T. Bayazitov,Stanislav S. Zakharenko,Amar Gajjar,Andrew M. Davidoff,Richard J. Gilbertson +15 more
TL;DR: This work shows that endothelial cells interact closely with self-renewing brain tumor cells and secrete factors that maintain these cells in a stem cell-like state, and proposes that brain CSCs are maintained within vascular niches that are important targets for therapeutic approaches.
Related Papers (5)
Inhibition of Hedgehog Signaling Enhances Delivery of Chemotherapy in a Mouse Model of Pancreatic Cancer
Kenneth P. Olive,Michael A. Jacobetz,Christian Davidson,Aarthi Gopinathan,Aarthi Gopinathan,Dominick J.O. McIntyre,Davina J. Honess,Basetti Madhu,Mae A. Goldgraben,Meredith E. Caldwell,David Allard,Kristopher K. Frese,Gina M. DeNicola,Gina M. DeNicola,Christine Feig,Chelsea Combs,Stephen P. Winter,Heather Ireland-Zecchini,Stefanie Reichelt,William J. Howat,Alex R. Chang,Mousumi Dhara,Lifu Wang,Lifu Wang,Felix Rückert,Robert Grützmann,Christian Pilarsky,Kamel Izeradjene,Sunil R. Hingorani,Pearl S. Huang,Susan E. Davies,William Plunkett,Merrill J. Egorin,Ralph H. Hruban,Nigel Whitebread,Karen McGovern,Julian Adams,Christine A. Iacobuzio-Donahue,John R. Griffiths,David A. Tuveson +39 more
Stromal elements act to restrain, rather than support, pancreatic ductal adenocarcinoma
Andrew D. Rhim,Andrew D. Rhim,Paul E. Oberstein,Dafydd H. Thomas,Emily T. Mirek,Carmine F. Palermo,Stephen A. Sastra,Erin N. Dekleva,Tyler Saunders,Claudia P. Becerra,Ian W. Tattersall,C. Benedikt Westphalen,Jan Kitajewski,Maite G. Fernandez-Barrena,Martin E. Fernandez-Zapico,Christine A. Iacobuzio-Donahue,Kenneth P. Olive,Ben Z. Stanger +17 more
Depletion of Carcinoma-Associated Fibroblasts and Fibrosis Induces Immunosuppression and Accelerates Pancreas Cancer with Reduced Survival.
Berna C. Özdemir,Berna C. Özdemir,Tsvetelina Pentcheva-Hoang,Julienne L. Carstens,Xiaofeng Zheng,Chia Chin Wu,Tyler R. Simpson,Hanane Laklai,Hikaru Sugimoto,Hikaru Sugimoto,Christoph Kahlert,Christoph Kahlert,Sergey V. Novitskiy,Ana De Jesus-Acosta,Padmanee Sharma,Pedram Heidari,Umar Mahmood,Lynda Chin,Harold L. Moses,Valerie M. Weaver,Anirban Maitra,James P. Allison,Valerie S. LeBleu,Valerie S. LeBleu,Raghu Kalluri,Raghu Kalluri +25 more