| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Tumor Biology |
Division of Hematology/Oncology, Department of Medicine, Mount Sinai School of Medicine, New York, New York 10029
After dissemination from a primary tumor, cancer cells may resume growth, leading to overt metastasis, or enter a state of protracted dormancy. However, mechanisms that determine their fate, or markers that predict it, are mostly unavailable. We previously showed that in HEp3 human head and neck carcinoma, the extracellular signal-regulated kinase (ERK)MAPK/p38SAPK activity ratio predicts whether the cells will proliferate or enter a state of dormancy in vivo. The proproliferative balance of high ERK/p38 ratio was induced by high urokinase (uPA) receptor (uPAR) expression, which activated 
5ß1-integrin and epidermal growth factor receptor. This signaling pathway was additionally enhanced by uPA binding to uPAR and fibronectin binding to 5ß1-integrin. We tested whether the ERK/p38 balance is predictive of in vivo behavior in other cancer cell types and whether altering the balance will shift their phenotype between proliferation and dormancy. ERK and p38 activities were determined using either phospho-specific monoclonal antibodies or a trans-reporting system where GAL4-Elk and GAL4-CHOP trans-activation of luciferase gene served as reporters for ERK and p38 activities, respectively. We show that in breast, prostate, melanoma, and fibrosarcoma cell lines, the level of active phospho-ERK and the ERK/p38 activity ratio predict for the in vivo behavior in 
90% of the cell lines tested. Modulation of ERK/p38 activity ratio by multiple pharmacological and genetic interventions confirms that high ERK/p38 ratio favors tumor growth, whereas high p38/ERK ratio induces tumor growth arrest (dormancy) in vivo and that ERK is negatively regulated by p38. A melanoma cell line appeared to have developed an escape mechanism to avoid the growth inhibitory effect of high p38 activity. Mechanistic analysis implicated high uPAR expression and its interaction with and activation of 5ß1-integrin as determinants of the in vivo growth promoting high ERK/p38 ratio in several cell lines. The small GTPase, Cdc42, was implicated in activation of p38 and growth arrest. These results suggest that even cells that originate in advanced cancers retain a degree of dependence on surface receptors and matrix for their proliferative signals in vivo and provide a therapeutic opportunity to change their phenotype from tumorigenic to dormant.
This article has been cited by other articles:
|
|
 |
|
  X. Cheng, Z. Shen, L. Yin, S.-H. Lu, and Y. Cui ECRG2 Regulates Cell Migration/Invasion through Urokinase-type Plasmin Activator Receptor (uPAR)/{beta}1 Integrin Pathway J. Biol. Chem., November 6, 2009; 284(45): 30897 - 30906. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. P. Adam, A. George, D. Schewe, P. Bragado, B. V. Iglesias, A. C. Ranganathan, A. Kourtidis, D. S. Conklin, and J. A. Aguirre-Ghiso Computational Identification of a p38SAPK-Regulated Transcription Factor Network Required for Tumor Cell Quiescence Cancer Res., July 15, 2009; 69(14): 5664 - 5672. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Ying, A. Lau, C. M. Alvira, R. West, G. M. Cann, B. Zhou, C. Kinnear, E. Jan, P. Sarnow, M. Van de Rijn, et al. LC3-mediated fibronectin mRNA translation induces fibrosarcoma growth by increasing connective tissue growth factor J. Cell Sci., May 1, 2009; 122(9): 1441 - 1451. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. M. Schewe and J. A. Aguirre-Ghiso Inhibition of eIF2{alpha} Dephosphorylation Maximizes Bortezomib Efficiency and Eliminates Quiescent Multiple Myeloma Cells Surviving Proteasome Inhibitor Therapy Cancer Res., February 15, 2009; 69(4): 1545 - 1552. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. M. Schewe and J. A. Aguirre-Ghiso ATF6{alpha}-Rheb-mTOR signaling promotes survival of dormant tumor cells in vivo PNAS, July 29, 2008; 105(30): 10519 - 10524. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A Vincent-Salomon, F C Bidard, and J Y Pierga Bone marrow micrometastasis in breast cancer: review of detection methods, prognostic impact and biological issues J. Clin. Pathol., May 1, 2008; 61(5): 570 - 576. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Sun, F. Wu, F. Sun, and P. Huang Adenosine Promotes IL-6 Release in Airway Epithelia J. Immunol., March 15, 2008; 180(6): 4173 - 4181. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. M. K. Pulukuri, B. Gorantla, and J. S. Rao Inhibition of Histone Deacetylase Activity Promotes Invasion of Human Cancer Cells through Activation of Urokinase Plasminogen Activator J. Biol. Chem., December 7, 2007; 282(49): 35594 - 35603. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X. Zheng, X.-X. Cui, G. E. Avila, M.-T. Huang, Y. Liu, J. Patel, A. N. T. Kong, R. Paulino, W. J. Shih, Y. Lin, et al. Atorvastatin and Celecoxib Inhibit Prostate PC-3 Tumors in Immunodeficient Mice Clin. Cancer Res., September 15, 2007; 13(18): 5480 - 5487. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J.F. Schindler, J.B. Monahan, and W.G. Smith p38 Pathway Kinases as Anti-inflammatory Drug Targets Journal of Dental Research, September 1, 2007; 86(9): 800 - 811. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y.-H. Hsieh, T.-T. Wu, C.-Y. Huang, Y.-S. Hsieh, J.-M. Hwang, and J.-Y. Liu p38 Mitogen-Activated Protein Kinase Pathway Is Involved in Protein Kinase C{alpha}-Regulated Invasion in Human Hepatocellular Carcinoma Cells Cancer Res., May 1, 2007; 67(9): 4320 - 4327. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. G. Papatsoris, M. V. Karamouzis, and A. G. Papavassiliou The power and promise of "rewiring" the mitogen-activated protein kinase network in prostate cancer therapeutics Mol. Cancer Ther., March 1, 2007; 6(3): 811 - 819. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Wei, C.-H. Tang, Y. Kim, L. Robillard, F. Zhang, M. C. Kugler, and H. A. Chapman Urokinase Receptors Are Required for {alpha}5beta1 Integrin-mediated Signaling in Tumor Cells J. Biol. Chem., February 9, 2007; 282(6): 3929 - 3939. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. M. K. Pulukuri, N. Estes, J. Patel, and J. S. Rao Demethylation-Linked Activation of Urokinase Plasminogen Activator Is Involved in Progression of Prostate Cancer Cancer Res., February 1, 2007; 67(3): 930 - 939. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Yin, F. Vreeland, L. J. Schaaf, R. Millham, B. A. Duncan, and A. Sharma Clinical Pharmacodynamic Effects of the Growth Hormone Receptor Antagonist Pegvisomant: Implications for Cancer Therapy Clin. Cancer Res., February 1, 2007; 13(3): 1000 - 1009. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Z. Hashmi, W. Hakim, E. A. Kruglov, A. Watanabe, W. Watkins, J. A. Dranoff, and W. Z. Mehal Adenosine inhibits cytosolic calcium signals and chemotaxis in hepatic stellate cells Am J Physiol Gastrointest Liver Physiol, January 1, 2007; 292(1): G395 - G401. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Kono, I. S. Dunn, P. J. Durda, D. Butera, L. B. Rose, T. J. Haggerty, E. M. Benson, and J. T. Kurnick Role of the Mitogen-Activated Protein Kinase Signaling Pathway in the Regulation of Human Melanocytic Antigen Expression Mol. Cancer Res., October 1, 2006; 4(10): 779 - 792. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L.-J. Zhao, X.-L. Zhang, P. Zhao, J. Cao, M.-M. Cao, S.-Y. Zhu, H.-Q. Liu, and Z.-T. Qi Up-regulation of ERK and p38 MAPK signaling pathways by hepatitis C virus E2 envelope protein in human T lymphoma cell line J. Leukoc. Biol., August 1, 2006; 80(2): 424 - 432. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. A. Madsen, E. I. Deryugina, S. Niessen, B. F. Cravatt, and J. P. Quigley Activity-based Protein Profiling Implicates Urokinase Activation as a Key Step in Human Fibrosarcoma Intravasation J. Biol. Chem., June 9, 2006; 281(23): 15997 - 16005. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Chaurasia, J. A. Aguirre-Ghiso, O. D. Liang, H. Gardsvoll, M. Ploug, and L. Ossowski A Region in Urokinase Plasminogen Receptor Domain III Controlling a Functional Association with {alpha}5beta1 Integrin and Tumor Growth J. Biol. Chem., May 26, 2006; 281(21): 14852 - 14863. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. K. Rasiah, J. G. Kench, M. Gardiner-Garden, A. V. Biankin, D. Golovsky, P. C. Brenner, R. Kooner, G. F. O'Neill, J. J. Turner, W. Delprado, et al. Aberrant neuropeptide y and macrophage inhibitory cytokine-1 expression are early events in prostate cancer development and are associated with poor prognosis. Cancer Epidemiol. Biomarkers Prev., April 1, 2006; 15(4): 711 - 716. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. A. Kruglov, R. A. Nathanson, T. Nguyen, and J. A. Dranoff Secretion of MCP-1/CCL2 by bile duct epithelia induces myofibroblastic transdifferentiation of portal fibroblasts Am J Physiol Gastrointest Liver Physiol, April 1, 2006; 290(4): G765 - G771. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Angelucci, G. L. Gravina, N. Rucci, D. Millimaggi, C. Festuccia, P. Muzi, A. Teti, C. Vicentini, and M. Bologna Suppression of EGF-R signaling reduces the incidence of prostate cancer metastasis in nude mice. Endocr. Relat. Cancer, March 1, 2006; 13(1): 197 - 210. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. N. Naumov, E. Bender, D. Zurakowski, S.-Y. Kang, D. Sampson, E. Flynn, R. S. Watnick, O. Straume, L. A. Akslen, J. Folkman, et al. A model of human tumor dormancy: an angiogenic switch from the nonangiogenic phenotype. J Natl Cancer Inst, March 1, 2006; 98(5): 316 - 325. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. A. Hickson, D. Huo, D. J. Vander Griend, A. Lin, C. W. Rinker-Schaeffer, and S. D. Yamada The p38 Kinases MKK4 and MKK6 Suppress Metastatic Colonization in Human Ovarian Carcinoma Cancer Res., February 15, 2006; 66(4): 2264 - 2270. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. C. Ranganathan, L. Zhang, A. P. Adam, and J. A. Aguirre-Ghiso Functional Coupling of p38-Induced Up-regulation of BiP and Activation of RNA-Dependent Protein Kinase-Like Endoplasmic Reticulum Kinase to Drug Resistance of Dormant Carcinoma Cells Cancer Res., February 1, 2006; 66(3): 1702 - 1711. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. J. Vander Griend, M. Kocherginsky, J. A. Hickson, W. M. Stadler, A. Lin, and C. W. Rinker-Schaeffer Suppression of Metastatic Colonization by the Context-Dependent Activation of the c-Jun NH2-Terminal Kinase Kinases JNKK1/MKK4 and MKK7 Cancer Res., December 1, 2005; 65(23): 10984 - 10991. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. M. Pulukuri, C. S. Gondi, S. S. Lakka, A. Jutla, N. Estes, M. Gujrati, and J. S. Rao RNA Interference-directed Knockdown of Urokinase Plasminogen Activator and Urokinase Plasminogen Activator Receptor Inhibits Prostate Cancer Cell Invasion, Survival, and Tumorigenicity in Vivo J. Biol. Chem., October 28, 2005; 280(43): 36529 - 36540. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. J. Renukaradhya, T. J. R. Webb, M. A. Khan, Y. L. Lin, W. Du, J. Gervay-Hague, and R. R. Brutkiewicz Virus-Induced Inhibition of CD1d1-Mediated Antigen Presentation: Reciprocal Regulation by p38 and ERK J. Immunol., October 1, 2005; 175(7): 4301 - 4308. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Zhu, X. Zhong, S. Zheng, Z. Ge, Q. Du, and S. Zhang Transformation of immortalized colorectal crypt cells by microcystin involving constitutive activation of Akt and MAPK cascade Carcinogenesis, July 1, 2005; 26(7): 1207 - 1214. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Gargiulo, I. Longanesi-Cattani, K. Bifulco, P. Franco, R. Raiola, P. Campiglia, P. Grieco, G. Peluso, M. P. Stoppelli, and M. V. Carriero Cross-talk between fMLP and Vitronectin Receptors Triggered by Urokinase Receptor-derived SRSRY Peptide J. Biol. Chem., July 1, 2005; 280(26): 25225 - 25232. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. E. McMullen, P. W. Bryant, C. C. Glembotski, P. A. Vincent, and K. M. Pumiglia Activation of p38 Has Opposing Effects on the Proliferation and Migration of Endothelial Cells J. Biol. Chem., June 3, 2005; 280(22): 20995 - 21003. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Jo, K. S. Thomas, N. Marozkina, T. J. Amin, C. M. Silva, S. J. Parsons, and S. L. Gonias Dynamic Assembly of the Urokinase-type Plasminogen Activator Signaling Receptor Complex Determines the Mitogenic Activity of Urokinase-type Plasminogen Activator J. Biol. Chem., April 29, 2005; 280(17): 17449 - 17457. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. F. Deroanne, D. Hamelryckx, T. T. G. Ho, C. A. Lambert, P. Catroux, C. M. Lapiere, and B. V. Nusgens Cdc42 downregulates MMP-1 expression by inhibiting the ERK1/2 pathway J. Cell Sci., March 15, 2005; 118(6): 1173 - 1183. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. M. Kumar, G. Acs, D. Fang, M. Herlyn, D. E. Elder, and X. Xu Functional Erythropoietin Autocrine Loop in Melanoma Am. J. Pathol., March 1, 2005; 166(3): 823 - 830. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z. Lou, S. O'Reilly, H. Liang, V. M. Maher, S. D. Sleight, and J. J. McCormick Down-Regulation of Overexpressed Sp1 Protein in Human Fibrosarcoma Cell Lines Inhibits Tumor Formation Cancer Res., February 1, 2005; 65(3): 1007 - 1017. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Wei, R.-P. Czekay, L. Robillard, M. C. Kugler, F. Zhang, K. K. Kim, J.-p. Xiong, M. J. Humphries, and H. A. Chapman Regulation of {alpha}5{beta}1 integrin conformation and function by urokinase receptor binding J. Cell Biol., January 31, 2005; 168(3): 501 - 511. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. J. Waters and B. L. Conway-Campbell The oncogenic potential of autocrine human growth hormone in breast cancer PNAS, October 19, 2004; 101(42): 14992 - 14993. [Full Text] [PDF]
|
|
|
|
|
|
J. A. Aguirre-Ghiso, L. Ossowski, and S. K. Rosenbaum Green Fluorescent Protein Tagging of Extracellular Signal-Regulated Kinase and p38 Pathways Reveals Novel Dynamics of Pathway Activation during Primary and Metastatic Growth Cancer Res., October 15, 2004; 64(20): 7336 - 7345. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. A. Dranoff, M. Ogawa, E. A. Kruglov, M. D. A. Gaca, J. Sevigny, S. C. Robson, and R. G. Wells Expression of P2Y nucleotide receptors and ectonucleotidases in quiescent and activated rat hepatic stellate cells Am J Physiol Gastrointest Liver Physiol, August 1, 2004; 287(2): G417 - G424. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. Qi, J. Tang, R. Pramanik, R. M. Schultz, S. Shirasawa, T. Sasazuki, J. Han, and G. Chen p38 MAPK Activation Selectively Induces Cell Death in K-ras-mutated Human Colon Cancer Cells through Regulation of Vitamin D Receptor J. Biol. Chem., May 21, 2004; 279(21): 22138 - 22144. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Liu, S. Yin, N. Reddy, C. Spencer, and S. Sheng Bax Mediates the Apoptosis-Sensitizing Effect of Maspin Cancer Res., March 1, 2004; 64(5): 1703 - 1711. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Ossowski, J. Aguirre Ghiso, D. Liu, Y. Estrada, and S. Rosenbaum The role of ERK and p38 in regulation of tumor dormancy. AACR Meeting Abstracts, March 1, 2004; 2004(1): 1318 - 1319. [Abstract]
|
|
|
|
|
|
R. M. Klein, M. Zheng, A. Ambesi, L. Van De Water, and P. J. McKeown-Longo Stimulation of extracellular matrix remodeling by the first type III repeat in fibronectin J. Cell Sci., November 15, 2003; 116(22): 4663 - 4674. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. R. Welch and K. W. Hunter A New Member of the Growing Family of Metastasis Suppressors Identified in Prostate Cancer J Natl Cancer Inst, June 18, 2003; 95(12): 839 - 841. [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Cancer Research | Clinical Cancer Research |
| Cancer Epidemiology Biomarkers & Prevention | Molecular Cancer Therapeutics |
| Molecular Cancer Research | Cancer Prevention Research |
| Cancer Prevention Journals Portal | Cancer Reviews Online |
| Annual Meeting Education Book | Meeting Abstracts Online |
