Vitamin D Receptor-Mediated Stromal Reprogramming Suppresses Pancreatitis and Enhances Pancreatic Cancer Therapy

被引：944

作者：

Sherman, Mara H. ^{[1
]}

Yu, Ruth T. ^{[1
]}

Engle, Dannielle D. ^{[2
]}

Ding, Ning ^{[1
]}

Atkins, Annette R. ^{[1
]}

Tiriac, Herve ^{[2
]}

Collisson, Eric A. ^{[3
]}

Connor, Frances ^{[4
]}

Van Dyke, Terry ^{[5
]}

Kozlov, Serguei ^{[6
]}

Martin, Philip ^{[6
]}

Tseng, Tiffany W. ^{[1
]}

Dawson, David W. ^{[7
]}

Donahue, Timothy R. ^{[7
]}

Masamune, Atsushi ^{[8
]}

Shimosegawa, Tooru ^{[8
]}

Apte, Minoti V. ^{[9
]}

Wilson, Jeremy S. ^{[9
]}

Ng, Beverly ^{[10
,11
]}

Lau, Sue Lynn ^{[10
,12
,13
]}

Gunton, Jenny E. ^{[10
,11
,12
,13
]}

Wahl, Geoffrey M. ^{[1
]}

Hunter, Tony ^{[14
]}

Drebin, Jeffrey A. ^{[15
]}

O'Dwyer, Peter J. ^{[16
]}

Liddle, Christopher ^{[17
,18
]}

Tuveson, David A. ^{[2
]}

Downes, Michael ^{[1
]}

Evans, Ronald M. ^{[1
,19
]}

机构：

[1] Salk Inst Biol Studies, Gene Express Lab, La Jolla, CA 92037 USA

[2] Cold Spring Harbor Lab, Cold Spring Harbor, NY 11724 USA

[3] Univ Calif San Francisco, Dept Med Hematol & Oncol, San Francisco, CA 94143 USA

[4] Canc Res UK Cambridge Res Inst, Li Ka Shing Ctr, Cambridge CB2 0RE, England

[5] NCI, Ctr Adv Preclin Res, Frederick, MD 21702 USA

[6] Leidos Biomed Inc, Frederick Natl Lab Canc Res, Ctr Adv Preclin Res, Frederick, MD 21702 USA

[7] Univ Calif Los Angeles, David Geffen Sch Med, Jonsson Comprehens Canc Ctr, Los Angeles, CA 90095 USA

[8] Tohoku Univ, Grad Sch Med, Div Gastroenterol, Sendai, Miyagi 9808574, Japan

[9] Univ New S Wales, South Western Sydney Clin Sch, Fac Med, Pancreat Res Grp, Sydney, NSW 2052, Australia

[10] Garvan Inst Med Res, Diabet & Transcript Factors Grp, Sydney, NSW 2010, Australia

[11] Univ New S Wales, St Vincents Clin Sch, Sydney, NSW 2052, Australia

[12] Univ Sydney, Fac Med, Sydney, NSW 2052, Australia

[13] Westmead Hosp, Dept Endocrinol & Diabet, Sydney, NSW 2145, Australia

[14] Salk Inst Biol Studies, Mol & Cell Biol Lab, La Jolla, CA 92037 USA

[15] Hosp Univ Penn, Dept Surg, Philadelphia, PA 19104 USA

[16] Hosp Univ Penn, Abramson Canc Ctr, Philadelphia, PA 19104 USA

[17] Westmead Millennium Inst, Storr Liver Unit, Westmead, NSW 2145, Australia

[18] Univ Sydney, Westmead Hosp, Westmead, NSW 2145, Australia

[19] Salk Inst Biol Studies, Howard Hughes Med Inst, La Jolla, CA 92037 USA

来源：

CELL | 2014年 / 159卷 / 01期

基金：

日本学术振兴会; 英国医学研究理事会;

关键词：

DUCTAL ADENOCARCINOMA; STELLATE CELLS; MOUSE MODEL; TUMOR-STROMA; MICE LACKING; IN-VIVO; PROGRESSION; GROWTH; FIBROBLASTS; GEMCITABINE;

D O I：

10.1016/j.cell.2014.08.007

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

The poor clinical outcome in pancreatic ductal adenocarcinoma (PDA) is attributed to intrinsic chemoresistance and a growth-permissive tumor micro-environment. Conversion of quiescent to activated pancreatic stellate cells (PSCs) drives the severe stromal reaction that characterizes PDA. Here, we reveal that the vitamin D receptor (VDR) is expressed in stroma from human pancreatic tumors and that treatment with the VDR ligand calcipotriol markedly reduced markers of inflammation and fibrosis in pancreatitis and human tumor stroma. We show that VDR acts as a master transcriptional regulator of PSCs to reprise the quiescent state, resulting in induced stromal remodeling, increased intratumoral gemcitabine, reduced tumor volume, and a 57% increase in survival compared to chemotherapy alone. This work describes a molecular strategy through which transcriptional reprogramming of tumor stroma enables chemotherapeutic response and suggests vitamin D priming as an adjunct in PDA therapy.

引用

页码：80 / 93

页数：14

共 62 条

[1] Connective tissue growth factor-specific antibody attenuates tumor growth, metastasis, and angiogenesis in an orthotopic mouse model of pancreatic cancer [J].

Aikawa, Takuma ;

Gunn, Jason ;

Spong, Suzanne M. ;

Klaus, Stephen J. ;

Korc, Murray .

MOLECULAR CANCER THERAPEUTICS, 2006, 5 (05) :1108-1116

[2] Unraveling the therapeutic potential of the Hedgehog pathway in cancer [J].

Amakye, Dereck ;

Jagani, Zainab ;

Dorsch, Marion .

NATURE MEDICINE, 2013, 19 (11) :1410-1422

[3] Periacinar stellate shaped cells in rat pancreas: identification, isolation, and culture [J].

Apte, MV ;

Haber, PS ;

Applegate, TL ;

Norton, ID ;

McCaughan, GW ;

Korsten, MA ;

Pirola, RC ;

Wilson, JS .

GUT, 1998, 43 (01) :128-133

[4] Sonic Hedgehog Promotes Desmoplasia in Pancreatic Cancer [J].

Bailey, Jennifer M. ;

Swanson, Benjamin J. ;

Hamada, Tomofumi ;

Eggers, John P. ;

Singh, Pankaj K. ;

Caffery, Thomas ;

Ouellette, Michel M. ;

Hollingsworth, Michael A. .

CLINICAL CANCER RESEARCH, 2008, 14 (19) :5995-6004

[5] A novel method for quantification of gemcitabine and its metabolites 2',2'-difluorodeoxyuridine and gemcitabine triphosphate in tumour tissue by LC-MS/MS: comparison with 19F NMR spectroscopy [J].

Bapiro, Tashinga E. ;

Richards, Frances M. ;

Goldgraben, Mae A. ;

Olive, Kenneth P. ;

Madhu, Basetti ;

Frese, Kristopher K. ;

Cook, Natalie ;

Jacobetz, Michael A. ;

Smith, Donna-Michelle ;

Tuveson, David A. ;

Griffiths, John R. ;

Jodrell, Duncan I. .

CANCER CHEMOTHERAPY AND PHARMACOLOGY, 2011, 68 (05) :1243-1253

[6] Both p16Ink4a and the p19Arf-p53 pathway constrain progression of pancreatic adenocarcinoma in the mouse [J].

Bardeesy, N ;

Aguirre, AJ ;

Chu, GC ;

Cheng, KH ;

Lopez, LV ;

Hezel, AF ;

Feng, B ;

Brennan, C ;

Weissleder, R ;

Mahmood, U ;

Hanahan, D ;

Redston, MS ;

Chin, L ;

DePinho, RA .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2006, 103 (15) :5947-5952

[7] Tumor-Derived Granulocyte-Macrophage Colony-Stimulating Factor Regulates Myeloid Inflammation and T Cell Immunity in Pancreatic Cancer [J].

Bayne, Lauren J. ;

Beatty, Gregory L. ;

Jhala, Nirag ;

Clark, Carolyn E. ;

Rhim, Andrew D. ;

Stanger, Ben Z. ;

Vonderheide, Robert H. .

CANCER CELL, 2012, 21 (06) :822-835

[8] Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis [J].

Bergers, G ;

Brekken, R ;

McMahon, G ;

Vu, TH ;

Itoh, T ;

Tamaki, K ;

Tanzawa, K ;

Thorpe, P ;

Itohara, S ;

Werb, Z ;

Hanahan, D .

NATURE CELL BIOLOGY, 2000, 2 (10) :737-744

[9] Stromal fibroblasts in cancer initiation and progression [J].

Bhowmick, NA ;

Neilson, EG ;

Moses, HL .

NATURE, 2004, 432 (7015) :332-337

[10] Why don't we get more cancer? A proposed role of the microenvironment in restraining cancer progression [J].

Bissell, Mina J. ;

Hines, William C. .

NATURE MEDICINE, 2011, 17 (03) :320-329

← 1 2 3 4 5 6 7 →