"Genomic Models of Functional Embryomas within Adult Neoplastic Cells".
Jeannette A. Hovsepian 1, and John H. Frenster 2
Divisions of 1 Diagnostic Imaging, and of
2 Medical Oncology
Stanford University School of Medicine, Stanford, California 94305,
USA
Phone: 650/367-6483, e-mail: hovsepianj@aol.com
, frensterjh@aol.com , http://www.embryomas.net/
Supported in part by a USPHS Research Career Development Award (CA-17857) from the National Cancer Institute.
Genomic analysis of vertebrate neoplasms often reveals the re-expression of exclusively-embryonic genes within neoplastic adult cells. Exclusively-embryonic genes are normally expressed during embryogenesis, but not again within normal adult cells. Other lifetime-embryonic genes are less constrained, and are co-expressed with adult genes within normal adult cells. The re-expression of one exclusively-embryonic gene within one normal adult cell is sufficient to initiate an adult neoplasm: Okito K, et al, “Generation of germline-competent induced pluripotent stem cells”, Nature 448: 313-317 (July19, 2007).
Large embryonic gene networks are often re-expressed intact, as in the epithelial-mesenchymal transition (EMT) mediating metastases from a primary neoplasm. The sizes of such networks expressed during metastases rival the sizes of the entire genomes of some non-vertebrate species in complexity: Sarrió D, et al, "Epithelial-Mesenchymal Transition in Breast Cancer Relates to the Basal-like Phenotype", Cancer Research 68, 989-997, February 15, 2008.
The accumulation of re-expressed exclusively-embryonic genes within a neoplastic adult cell acts as an embryoma, and often occurs in a context of diminished embryonic controls within the adult cell: Takamizawa J, et al, “Reduced expression of the let-7 microRNAs in human lung cancers in association with shortened postoperative survival”, Cancer Research 64: 3753-3756 (2004); Johnson SM, et al, “RAS is regulated by the let-7 microRNA family”, Cell 120: 635-647 (2005).
The provision of normal embryonic control molecules to such embryomas often permits a reversion of the neoplastic adult cells toward normality: Kumar MS, et al, "Suppression of non-small cell lung tumor development by the let-7 microRNA family", Proc. Natl. Acad. Sci. USA, 105: 3903-3908 (March 11, 2008).
These data strongly indicate that vertebrate adult neoplastic cells usually contain embryonic genes that are active in inappropriate transcription, and that such neoplastic transcription can be controlled by added specific embryonic ribo-regulator molecules.
1. Frenster JH, and Hovsepian JA, (2007)
“Models
of Embryonic Gene-Induced Initiation and Reversion of Adult Neoplasms”.
2. Frenster JH, and Hovsepian JA, (2008)
"Models
of Embryonic RNA Initiating and Reverting Adult Neoplasms".
3. Frenster JH, and Hovsepian JA, (2008)
"Micro-RNAs
and adult neoplasms of embryonic type".
4. Bernards R, (2008)
Perspective: "Cancer:
Entangled pathways".
5. Morris EJ, Ji J-Y, Yang F, Di Stefano L, Herr A, Moon N-S, Kwon
E-J, Haigis KM, Näär AM, and Dyson NJ, (2008)
"E2F1
represses b-catenin transcription and is antagonized
by both pRB and CDK8".
Supplementary Figure 1. Colorectal tumor cells accumulate features that suppress the activity of E2F1 and enhance the activity of b-catenin.
In normal cells canonical Wnt signaling drives the expression
of genes that are crucial for cell proliferation and survival, such as
c-MYC. E2F1 represents a potential brake on b-catenin
activity: E2F1 inhibits b-catenin-mediated
activation of c-MYC, and activates the expression of AXIN1, AXIN2
and SIAH1, resulting in b-catenin degradation.
By amplifying and/or overexpressing CDK8 and Rb, and by expressing c-myc-induced
miR17-92, colorectal tumor cells select for mechanisms that limit the
activity of E2F1 and tip the balance towards b-catenin-driven
proliferation. CDK8 may be particularly important in this regard because
it both suppresses E2F1-dependent transcription and enhances
b-catenin-dependent transcription.
6. Firestein R, and Hahn WC, (2009)
"Revving
the Throttle on an Oncogene: CDK8 Takes the Driver Seat",
7. Firestein R, Shima K, Nosho K, Irahara N, Baba Y, Bojarski E, Giovannucci EL, Charles S. Fuchs CS, and Ogino S, (2009), "CDK8 expression in 470 colorectal cancers in relation to b-catenin activation, other molecular alterations and patient survival".
8. Varlakhanova NV, and Knoepfler PS, (2009)
"Acting
Locally and Globally: Myc's Ever-Expanding Roles on Chromatin".
9, Kota J, Chivukula RR, O'Donnell KA, Wentzel EA, Montgomery
CL, Hwang H-W, Chang T-C, Vivekanandan P, Torbenson M, Clark KR, Mendell
JR, and Mendel JT (June, 2009)
"Therapeutic microRNA Delivery Suppresses Tumorigenesis in a Murine
Liver Cancer Model",
Cell,
Volume 137, Issue 6, 1005-1017, 12 June 2009,
10. Shimono Y, Zabala M, Cho RW, Lobo N, Dalerba P, Qian D, Diehn
M, Liu H, Panula SP, Chiao E, Dirbas FM, Somlo G, Reijo Pera RA, Lao K
and Clarke MF, (2009).
"Downregulation
of miRNA-200c Links Breast Cancer Stem Cells with Normal Stem Cells".
11. Chan KS, Espinosa I, Chao M, Wong D, Ailles L, Diehn M, Gill
H, Presti J Jr, Chang HY, van de Rijn M, Shortliffe L, Weissman IL. (2009).
"Identification,
molecular characterization, clinical prognosis, and therapeutic targeting
of human bladder tumor-initiating cells".
12. Katoh M, and Katoh M, (2009).
"Integrative genomic
analyses of WNT11: Transcriptional mechanisms based on canonical WNT signals
and GATA transcription factors signaling",
13. Von Hoff DD, Lorusso PM, Rudin CM, Reddy JC, Yauch RL, Tibes
R, Weiss GJ, Borad MJ, Hann CL, Brahmer JR, Mackey HM, Lum BL, Darbonne
WC, Marsters JC Jr, de Sauvage FJ, Low JA. (2009).
"Inhibition of
the Hedgehog Pathway in Advanced Basal-Cell Carcinoma",
14. Strizzi L, Hardy KM, Seftor EA, Costa FF, Kirschmann DA, Seftor
RE, Postovit LM, Hendrix MJ., (2009).
"Development and
cancer: at the crossroads of Nodal and Notch signaling."
15. Mishra PJ, and Merlino G, (2009).
"MicroRNA reexpression
as differentiation therapy in cancer".
16. Taulli R, Bersani F, Foglizzo V, Linari A, Vigna E, Ladanyi M,
Tuschl T, and Ponzetto C, (2009).
"The muscle-specific
microRNA miR-206 blocks human rhabdomyosarcoma growth in xenotransplanted
mice by promoting myogenic differentiation".
17. Koslowski M, Türeci O, Biesterfeld S, Seitz G, Huber
C, and Sahin U, (2009).
"Selective Activation
of Trophoblast-specific PLAC1 in Breast Cancer by CCAAT/Enhancer-binding
Protein b (C/EBPb)
Isoform 2".
18. Tchabo NE, Mhawech-Fauceglia P, Caballero OL, Villella J, Beck
AF, Miliotto AJ, Liao J, Andrews C, Lele S, Old LJ, and Odunsi K, (2009).
"Expression
and serum immunoreactivity of developmentally restricted differentiation
antigens in epithelial ovarian cancer".
19. Ooi CH, Ivanova T, Wu J, Lee M, Tan IB, Tao J, Ward L, Koo JH,
Gopalakrishnan V, Zhu Y, Cheng LL, Lee J, Rha SY, Chung HC, Ganesan K,
So J, Soo KC, Lim D, Chan WH, Wong WK, Bowtell D, Yeoh KG, Grabsch
H, Boussioutas A, and Tan P, (2009).
"Oncogenic Pathway
Combinations Predict Clinical Prognosis in Gastric Cancer".
20. Valastyan S, Benaich N, Chang A, Reinhardt F, and Weinberg RA,
(2009).
"Concomitant
suppression of three target genes can explain the impact of a microRNA
on metastasis".
21. Li L, Feng T, Lian Y, Zhang G, Garen A, and Song X, (2009).
"Role of human noncoding
RNAs in the control of tumorigenesis".
22. Kim HH, Kuwano Y, Srikantan S, Lee EK, Martindale JL, and Gorospe
M, (2009).
"HuR recruits let-7/RISC
to repress c-Myc expression".
23. Thiery JP, Acloque H, Huang RYJ, and Nieto MA, (2009).
"Epithelial-Mesenchymal
Transitions in Development and Disease".
24. Kessler JD, Hasegawa H, Brun SN, Emmenegger BA, Yang Z-J, Dutton
JW, Wang F, Wechsler-Reya RJ, (2009).
"N-myc alters
the fate of preneoplastic cells in a mouse model of medulloblastoma".
25. Navin N, Krasnitz A, Rodgers L, Cook K, Meth J, Kendal J, Riggs
M, Eberling Y, Troge J, Grubor V, Levy D, Lundin P, Månér
S, Zetterberg A, Hicks J, and Wigler M, (2009).
"Inferring tumor
progression from genomic heterogeneity".
1. Each cell retains all of its embryonic genes for a lifetime.
2. Controls for embryonic genes are often absent in adults.
3. Uncontrolled embryonic genes can replicate wildly.
4. Replicating genes participate in intra-cellular competition.
5. The basis for gene competition is selective transcription.
6. MicroRNAs can reprogram embryomic transcription.
7. Gene reprogramming can produce normal phenotypes.
8. Normal phenotypes can by-pass chromosomal lesions.
9. MicroRNA therapy may need to be permanent.
10. Transplantation of microRNAs could be preferred.
December 7, 2009.
Up-dated: http://www.embryomas.net#Conclusions
Links to Current
Research in Euchromatin:
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A Brief History of Activator RNA:
"Ultrastructural
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(PowerPoint Presentation).
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For Further Information and Feedback:
Jeannette A. Hovsepian, M.D.
E-mail: frensasc@ix.netcom.com
Phone: +1 650 367 6483