Dynamical studies of cellular signaling networks in cancers

Li Xiang; Liu Feng; Shuai Jian-Wei

doi:10.7498/aps.65.178704

Abstract

Cancer, as a conundrum, is currently the biggest killer of human health. The major viewpoint of carcinogenesis is owing to somatic gene mutations. Based on such a viewpoint and the development of gene sequencing technology, extensive genomic alterations in cancer genomes have been identified. How to develop a better understanding of the link between gene mutations and carcinogenesis as well as efficient clinical cancer therapy is therefore a major challenge. Weinberg and Hanahan have suggested 10 hallmarks of cancer. The hallmarks are highly regulated by the corresponding signaling pathways. Thus, cancer itself is also a disease of dysfunction of signal transduction pathways related to multiple fundamental cell processes, including proliferation, differentiation, apoptosis, invasion and so on. Despite the signaling pathways are extremely complex in cancer cells, one can still focus on the signaling networks that govern the corresponding cell processes for modeling to discuss its dynamics and regulation functions quantitatively. Systems biology provides appropriate approach to integrate the experimental data (clinical data) and signaling pathway for a comprehensive analysis, resulting in a further prediction for optimal therapy and drug discovery. In this paper, we review the recent progress of dynamical modeling of signaling networks by using systems biology approaches that help to exploring the mechanisms of carcinogenesis. We first discuss the motif dynamics of the signaling networks. The presented generic circuit model can be decomposed into two loops and the circuit can achieve tristability through four kinds of bifurcation scenarios when parameter values are varied in a wide range. Then, we show the relative well-studied core signaling networks that regulate the cell survival, apoptosis, proliferation, invasion and energy metabolism processes. For each fundamental cell process, we individually review the dynamics of corresponding signaling network based on the systems biology approaches, including the NF-B signaling pathway that regulates the cell survival process, the Ras signaling pathway that governs the cell proliferation process, the EMT and mitochondrial signaling pathway that modulate the cell invasion and apoptosis processes. Furthermore, two coupled signaling networks, i.e., the p53 and TNF- signaling networks are discussed. Lastly, we review the breast cancer and gastric cancer signaling networks which contain several fundamental cell processes. The potential contribution for cancer treatment is also suggested. These dynamical modeling based on the core signaling networks can facilitate the understanding of the mechanisms of carcinogenesis and provide us the possible clues and ideas of the cancer treatment and drug design. We believe more exciting research works in this field will be stimulated in the near future.

Keywords:

Authors and contacts

1.
Physics Department, Xiamen University, Xiamen 361005, China;
2.
Physics Department, Nanjing University, Nanjing 210093, China

Corresponding author: Shuai Jian-Wei, jianweishuai@xmu.edu.cn

Funds: Project supported by 973 program (No. 2013CB834104), the National Natural Science Foundation of China (Grant Nos. 31370830, 11175084, 31361163003) and the Fujian Province Funds for Leading Scientist in Universities.

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[51]	Li X, Chen Y, Qi H, Liu L, Shuai J 2016 Oncotarget 7 34599
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[56]	Barros R, Freund J N, David L, Almeida R 2012 Trends Mol. Med. 18 555
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[58]	Li S, Zhu X, Liu B, Wang G, Ao P 2015 Oncotarget 6 13607
[59]	Anderson A R, Quaranta V 2008 Nat. Rev. Cancer 8 227
[60]	Tomasetti C, Vogelstein B 2015 Science 347 78
[61]	Stratton M R, Campbell P J, Futreal P A 2009 Nature 458 719
[62]	Fischer K R, Durrans A, Lee S, Sheng J, Li F, Wong S T, Choi H, El Rayes T, Ryu S, Troeger J, Schwabe R F, Vahdat L T, Altorki N K, Mittal V, Gao D 2015 Nature 527 472
[63]	Li W, Kang Y 2016 Trends Cancer 2 65
[64]	Wei S C, Yang J 2016 Trends Cell Biol. 26 111
[65]	Bild A H, Potti A, Nevins J R 2006 Nat. Rev. Cancer 6 735
[66]	Wang Z, Deisboeck T S 2014 Drug Discov. Today 19 145

Cited By

[1]	Torre L, Bray F, Siegle R L, Ferlay J, Lortet-Tieulent J, Jemal A 2012 CA Cancer J. Clin. 65 87
[2]	Chen W, Zheng R, Baade P D, Zhang S, Zeng H, Bray F, Jemal A, Yu X Q, He J 2015 CA Cancer J. Clin. 66 115
[3]	Hanahan D and Weinberg R A 2011 Cell 144 646
[4]	Hanahan D and Weinberg R A 2000 Cell 100 57
[5]	Futreal P A, Kasprzyk A, Birney E, Mullikin J C, Wooster R, Stratton M R 2001 Nature 409 850
[6]	Parsons D W, Jones S, Zhang X Lin J C, Leary R J, Angenendt P, Mankoo P, Carter H, Siu I M, Gallia G L, Olivi A, McLendon R, Rasheed B A, Keir S, Nikolskaya T, Nikolsky Y, Busam D A, Tekleab H, Diaz L A Jr, Hartigan J, Smith D R, Strausberg R L, Marie S K, Shinjo S M, Yan H, Riggins G J, Bigner D D, Karchin R, Papadopoulos N, Parmigiani G, Vogelstein B, Velculescu V E, Kinzler K W 2008 Science 321 1807
[7]	Jones S, Zhang X, Parsons D W, Lin J C, Leary R J, Angenendt P, Mankoo P, Carter H, Kamiyama H, Jimeno A, Hong S M, Fu B, Lin M T, Calhoun E S, Kamiyama M, Walter K, Nikolskaya T, Nikolsky Y, Hartigan J, Smith D R, Hidalgo M, Leach S D, Klein A P, Jaffee E M, Goggins M, Maitra A, Iacobuzio-Donahue C, Eshleman J R, Kern S E, Hruban R H, Karchin R, Papadopoulos N, Parmigiani G, Vogelstein B, Velculescu V E, Kinzler K W 2008 Science 321 1801
[8]	Cancer Genome Atlas Research Network 2008 Nature 455 1061
[9]	Citri A, Yarden Y 2006 Nat. Rev. Mol. Cell Biol. 7 505
[10]	Hood L 2003 Mech. Ageing Dev. 124 9
[11]	Kitano H 2002 Science 295 1662
[12]	Iyengar R 2009 Sci. Signal 2 eg3
[13]	Friedman N, Linial M, Nachman I, Pe'er D 2000 J. Comput. Biol. 7 601
[14]	Kauffman S 1969 Nature 224 177
[15]	Schoeberl B, Eichler-Jonsson C, Gilles E D, Mller G 2002 Nat. Biotechnol. 20 370
[16]	Markevich N I, Tsyganov M A, Hoek J B, Kholodenko B N 2006 Mol. Syst. Biol. 2 61
[17]	Gillespie D T 2007 Annu. Rev. Phys. Chem. 58 35
[18]	Kirkpatrick S, Vecchi M P 1983 Science 220 671
[19]	Holland J H 1975 Adaptation in natural and artificial systems: an introductory analysis with applications to biology, control, and artificial intelligence (Ann Arbor: Control Artificial Intelligence University of Michigan Press)
[20]	Jerne N K 1974 Ann. Immunol. (Paris) 125C 373
[21]	Kreeger P K, Lauffenburger D A 2010 Carcinogenesis 31 2
[22]	Khalil I G, Hill C 2005 Curr. Opin. Oncol. 17 44
[23]	Aldridge B B, Burke J M, Lauffenburger D A, Sorger P K 2006 Nat. Cell. Biol. 8 1195
[24]	Zhang X P, Cheng Z, Liu F, Wang W 2007 Phys. Rev. E 76 031924.
[25]	Tian X J, Zhang X P, Liu F, Wang W 2009 Phys. Rev. E 80 011926
[26]	Lu M, Jolly M K, Levine H, Onuchic J N, Ben-Jacob E 2013 Proc. Natl. Acad. Sci. USA. 110 18144
[27]	Huang B, Xia Y, Liu F, Wang W 2016 Sci. Rep. 6 28096
[28]	Karin M, Lin A 2002 Nat. Immunol. 3 221
[29]	Perkins N D 2012 Nat. Rev. Cancer 12 121
[30]	Nakanishi C, Toi M 2005 Nat. Rev. Cancer 5 297
[31]	Karin M, Ben-Neriah Y 2000 Annu. Rev.Immunol. 18 621
[32]	Hoffmann A, Levchenko A, Scott M L, Baltimore D 2002 Science 298 1241
[33]	Parada L F, Tabin C J, Shih C, Weinberg R A 1982 Nature 297 474
[34]	Bos J L 1989 Cancer Res. 49 4682
[35]	Bos J L, Rehmann H, Wittinghofer A 2007 Cell 129 865
[36]	Stites E C, Trampont P C, Ma Z, Ravichandran K S 2007 Science 318 463
[37]	Thiery J P 2002 Nat. Rev. Cancer 2 442
[38]	Nakaya Y, Sheng G 2008 Dev. Growth Differ. 50 755
[39]	Morel A P, Livre M, Thomas C, Hinkal G, Ansieau S, Puisieux A 2008 PLoS One 3 e2888
[40]	Yang A D, Camp E R, Fan F, Shen L, Gray M J, Liu W, Somcio R, Bauer T W, Wu Y, Hicklin D J, Ellis L M 2006 Cancer Res. 66 46
[41]	De Craene B, Berx G 2013 Nat. Rev. Cancer 13 97
[42]	Steinway S N, Zaudo J G, Ding W, Rountree C B, Feith D J, Loughran T P Jr, Albert R 2014 Cancer Res. 74 5963
[43]	Tait S W, Green D R 2010 Nat. Rev. Mol. Cell Biol. 11 621
[44]	Zhao L, Sun T, Pei J, Ouyang Q 2015 Proc. Natl. Acad. Sci. USA. 112 E4046
[45]	Zhang X P, Liu F, Cheng Z, Wang W 2009 Proc. Natl. Acad. Sci. USA. 106 12245
[46]	Zhang X P, Liu F, Wang W 2011 Proc. Natl. Acad. Sci. USA. 108 8990
[47]	Beg A A, Sha W C, Bronson R T, Ghosh S, Baltimore D 1995 Nature 376 167
[48]	Neumann L, Pforr C, Beaudouin J, Pappa A, Fricker N, Krammer P H, Lavrik I N, Eils R 2010 Mol. Syst. Biol. 6 352
[49]	Takahashi R, Deveraux Q, Tamm I, Welsh K, Assa-Munt N, Salvesen G S, Reed J C 1998 J. Biol. Chem. 273 7787
[50]	Khoshnan A, Tindell C, Laux I, Bae D, Bennett B, Nel A E 2000 J. Immunol. 165 1743
[51]	Li X, Chen Y, Qi H, Liu L, Shuai J 2016 Oncotarget 7 34599
[52]	Futreal P A, Coin L, Marshall M, Down T, Hubbard T, Wooster R, Rahman N, Stratton M R 2004 Nat. Rev. Cancer 4 177
[53]	Kitano H 2004 Nat. Rev. Cancer. 4 227
[54]	Pujana M A, Han J D, Starita L M, Stevens K N, Tewari M, Ahn J S, Rennert G, Moreno V, Kirchhoff T, Gold B, Assmann V, Elshamy W M, Rual J F, Levine D, Rozek L S, Gelman R S, Gunsalus K C, Greenberg R A, Sobhian B, Bertin N, Venkatesan K, Ayivi-Guedehoussou N, Sol X, Hernndez P, Lzaro C, Nathanson K L, Weber B L, Cusick M E, Hill D E, Offit K, Livingston D M, Gruber S B, Parvin J D, Vidal M 2007 Nat. Genet. 39 1338
[55]	Lei X, Tian W, Zhu H, Chen T, Ao P 2015 Scientific Reports 5 13597
[56]	Barros R, Freund J N, David L, Almeida R 2012 Trends Mol. Med. 18 555
[57]	Tsukamoto T, Inada K, Tanaka H, Mizoshita T, Mihara M, Ushijima T, Yamamura Y, Nakamura S, Tatematsu M 2004 J. Cancer Res. Clin. Oncol. 130 135
[58]	Li S, Zhu X, Liu B, Wang G, Ao P 2015 Oncotarget 6 13607
[59]	Anderson A R, Quaranta V 2008 Nat. Rev. Cancer 8 227
[60]	Tomasetti C, Vogelstein B 2015 Science 347 78
[61]	Stratton M R, Campbell P J, Futreal P A 2009 Nature 458 719
[62]	Fischer K R, Durrans A, Lee S, Sheng J, Li F, Wong S T, Choi H, El Rayes T, Ryu S, Troeger J, Schwabe R F, Vahdat L T, Altorki N K, Mittal V, Gao D 2015 Nature 527 472
[63]	Li W, Kang Y 2016 Trends Cancer 2 65
[64]	Wei S C, Yang J 2016 Trends Cell Biol. 26 111
[65]	Bild A H, Potti A, Nevins J R 2006 Nat. Rev. Cancer 6 735
[66]	Wang Z, Deisboeck T S 2014 Drug Discov. Today 19 145

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