Computational Modeling of Pancreatic Cancer Reveals Kinetics of Metastasis Suggesting Optimum Treatment Strategies

被引：325

作者：

Haeno, Hiroshi ^{[6
,7
]}

Gonen, Mithat ^{[8
]}

Davis, Meghan B. ^{[1
]}

Herman, Joseph M. ^{[1
,5
]}

Iacobuzio-Donahue, Christine A. ^{[1
,2
,3
,4
]}

Michor, Franziska ^{[6
,7
]}

机构：

[1] Johns Hopkins Univ Hosp, Sol Goldman Pancreat Canc Res Ctr, Baltimore, MD 21231 USA

[2] Johns Hopkins Univ Hosp, Dept Pathol, Baltimore, MD 21231 USA

[3] Johns Hopkins Univ Hosp, Dept Oncol, Baltimore, MD 21231 USA

[4] Johns Hopkins Univ Hosp, Dept Surg, Baltimore, MD 21231 USA

[5] Johns Hopkins Univ Hosp, Dept Radiat Oncol & Mol Radiat Sci, Baltimore, MD 21231 USA

[6] Harvard Univ, Sch Publ Hlth, Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA

[7] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA

[8] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10065 USA

来源：

CELL | 2012年 / 148卷 / 1-2期

基金：

美国国家卫生研究院;

关键词：

PROGRESSION; CARCINOMA; SURVIVAL; DORMANCY; CHEMOTHERAPY; GEMCITABINE; INSTABILITY; RESECTION; DYNAMICS; PATTERNS;

D O I：

10.1016/j.cell.2011.11.060

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：

Pancreatic cancer is a leading cause of cancer-related death, largely due to metastatic dissemination. We investigated pancreatic cancer progression by utilizing a mathematical framework of metastasis formation together with comprehensive data of 228 patients, 101 of whom had autopsies. We found that pancreatic cancer growth is initially exponential. After estimating the rates of pancreatic cancer growth and dissemination, we determined that patients likely harbor metastases at diagnosis and predicted the number and size distribution of metastases as well as patient survival. These findings were validated in an independent database. Finally, we analyzed the effects of different treatment modalities, finding that therapies that efficiently reduce the growth rate of cells earlier in the course of treatment appear to be superior to upfront tumor resection. These predictions can be validated in the clinic. Our interdisciplinary approach provides insights into the dynamics of pancreatic cancer metastasis and identifies optimum therapeutic interventions.

引用

页码：362 / 375

页数：14

共 48 条

[41] Androgen-independent prostate cancer is a heterogeneous group of diseases: Lessons from a rapid autopsy program [J].

Shah, RB ;

Mehra, R ;

Chinnaiyan, AM ;

Shen, RL ;

Ghosh, D ;

Zhou, M ;

MacVicar, GR ;

Varambally, S ;

Harwood, J ;

Bismar, TA ;

Kim, R ;

Rubin, MA ;

Pienta, KJ .

CANCER RESEARCH, 2004, 64 (24) :9209-9216

[42]

Sherratt J A, 2001, Methods Mol Med, V57, P309, DOI 10.1385/1-59259-136-1:309

[43] Advanced pancreatic carcinoma: current treatment and future challenges [J].

Stathis, Anastasios ;

Moore, Malcolm J. .

NATURE REVIEWS CLINICAL ONCOLOGY, 2010, 7 (03) :163-172

[44] Massive Genomic Rearrangement Acquired in a Single Catastrophic Event during Cancer Development [J].

Stephens, Philip J. ;

Greenman, Chris D. ;

Fu, Beiyuan ;

Yang, Fengtang ;

Bignell, Graham R. ;

Mudie, Laura J. ;

Pleasance, Erin D. ;

Lau, King Wai ;

Beare, David ;

Stebbings, Lucy A. ;

McLaren, Stuart ;

Lin, Meng-Lay ;

McBride, David J. ;

Varela, Ignacio ;

Nik-Zainal, Serena ;

Leroy, Catherine ;

Jia, Mingming ;

Menzies, Andrew ;

Butler, Adam P. ;

Teague, Jon W. ;

Quail, Michael A. ;

Burton, John ;

Swerdlow, Harold ;

Carter, Nigel P. ;

Morsberger, Laura A. ;

Iacobuzio-Donahue, Christine ;

Follows, George A. ;

Green, Anthony R. ;

Flanagan, Adrienne M. ;

Stratton, Michael R. ;

Futreal, P. Andrew ;

Campbell, Peter J. .

CELL, 2011, 144 (01) :27-40

[45] AACR Centennial Series: The Biology of Cancer Metastasis: Historical Perspective [J].

Talmadge, James E. ;

Fidler, Isaiah J. .

CANCER RESEARCH, 2010, 70 (14) :5649-5669

[46] RETRACTED: Concomitant suppression of three target genes can explain the impact of a microRNA on metastasis (Retracted article. See vol. 29, pg. 686, 2015) [J].

Valastyan, Scott ;

Benaich, Nathan ;

Chang, Amelia ;

Reinhardt, Ferenc ;

Weinberg, Robert A. .

GENES & DEVELOPMENT, 2009, 23 (22) :2592-2597

[47] Telomere shortening is nearly universal in pancreatic intraepithelial neoplasia [J].

van Heek, NT ;

Meeker, AK ;

Kern, SE ;

Yeo, CJ ;

Lillemoe, KD ;

Cameron, JL ;

Offerhaus, GJA ;

Hicks, JL ;

Wilentz, RE ;

Goggins, MG ;

De Marzo, AM ;

Hruban, RH ;

Maitra, A .

AMERICAN JOURNAL OF PATHOLOGY, 2002, 161 (05) :1541-1547

[48] Distant metastasis occurs late during the genetic evolution of pancreatic cancer [J].

Yachida, Shinichi ;

Jones, Sian ;

Bozic, Ivana ;

Antal, Tibor ;

Leary, Rebecca ;

Fu, Baojin ;

Kamiyama, Mihoko ;

Hruban, Ralph H. ;

Eshleman, James R. ;

Nowak, Martin A. ;

Velculescu, Victor E. ;

Kinzler, Kenneth W. ;

Vogelstein, Bert ;

Iacobuzio-Donahue, Christine A. .

NATURE, 2010, 467 (7319) :1114-U126

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