Submitted on August 8, 2009 as abstract 691866, and presented on Tuesday, December 8, 2009 at Cancer Cells III #1640 at the 49th Annual Meeting of the American Society for Cell Biology in San Diego, California.

"Functional Embryomas as a Result of Embryonic Gene Re-expression".

John H. Frenster 1, and Jeannette A. Hovsepian 2,

Divisions of  1 Medical Oncology, and of  2 Diagnostic Imaging,
Stanford University School of Medicine, Stanford, California 94305, USA
Phone: 650/367-6483, e-mail:  frensterjh@aol.com ,  hovsepianj@aol.com , http://www.embryomas.net/

Supported in part by a USPHS Research Career Development Award (CA-17857) from the National Cancer Institute.


Abstract:

Clinical genetics can be defined as the mapping of specific DNA sequences, RNA transcripts, and protein agents onto specific phenotypes of disease states. As such, changes in DNA, RNA and/or proteins can be causal for a particular disease, especially one which is endogenous and progressive, such as human cancer.

Recent data increasingly reveal that large Epithelial-Mesenchymal Transition) (EMT) portions of the embryonic genome are re-expressed during mitosis of adult neoplasms (Thiery JP, Nature Rev. Cancer 2: 442-454, 2002). These EMT gene re-expressions as functional embryomas consist of a network of over 10 embryonic genes, some of which are normally expressed only during embryonic life (embryo-exclusive) (Weinberg RA, "The Biology of Cancer", Chapter 14.5, pp. 615-620, Garland Science, New York, NY, 2007).

More recent data in mice indicate that the expression of only one embryonic gene is sufficient to initiate a neoplastic state within one normal adult cell, progressing to a complete multicellular neoplasm and the metatstatic death of the animal (Okito K, et al, Nature 448: 313-317 (2007).

Still more recent data indicate that the administration of specific embryonic non-coding RNAs are sufficient to regress in-vivo adult neoplastic lung cancer cells in mice (Kumar MS, et al , Proc. Natl. Acad. Sci. U.S.A., 105: 3903-3908 (2008), and (Judge AD, et al, J. Clin. Invest. 119: 661-673 (2009).

The latter results have now been extended to specific RNA therapy of  in-vivo metastatic hepatocarcinomas in mice (Kota J, et al, Cell 137: 1005–1017 (2009), and are somewhat reminiscent of the clinical remissions of acute myelocytic leukemia noted after in-vivo intramarrow administrations of normal total marrow RNA in humans (DeCarvalho S, Nature, 197: 1077-1080, (1963).

These studies in the pathogenesis and therapy of neoplasms are most suprising and encouraging for further study.


Additional References:

a. Mishra PJ,  and Merlino G,
"MicroRNA reexpression as differentiation therapy in cancer".

b. . Taulli R, Bersani F, Foglizzo V, Linari A, Vigna E, Ladanyi M, Tuschl T, and Ponzetto C,
"The muscle-specific microRNA miR-206 blocks human rhabdomyosarcoma growth in xenotransplanted mice by promoting myogenic differentiation".

1. Frenster JH, and Hovsepian JA,  ( August, 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. Hovsepian JA, and Frenster JH,  ( 2009 )
      "Genomic Models of Functional Embryomas within Adult Neoplastic Cells".

5. Frenster JH,  (1999)
     "Oncogenes as Molecular Targets within Active Chromatin".
      Clinical Cancer Research, vol. 5, suppl. l, p. 3855s, (624), (November, 1999).

6. Hovsepian JA, and Frenster JH,  (2003)
"Euchromatin as an Extensile Force within Mammalian Cell Nuclei".


7. Hovsepian JA, and Frenster JH,  (2004)
"Reprogramming as an Approach to Neoplasms".


8. Koslowski M, Sahin U, Mitnacht-Kraus R, Seitz G, Huber C, and Türeci O, (October, 2007)
"A Placenta-Specific Gene Ectopically Activated in Many Human Cancers Is Essentially Involved in Malignant Cell Processes".

9. Berx G, Raspe E, Christfori G, Thiery JP, and Sleeman JP, (November, 2007)
"Pre-EMTing metastasis? Recapitulation of morphogenetic processes in cancer".
Clin Exp Metastasis, 2007;24(8):587-97, Epub 2007 Nov3.

10. Sarrió D, Rodriguez-Pinilla SM, Hardisson D, Cano A, Moreno-Bueno G, and Palacios J,  (Feb. 2008)
"Epithelial-Mesenchymal Transition in Breast Cancer Relates to the Basal-like Phenotype",
Cancer Research 68, 989-997, February 15, 2008.

11. Haigis KM, Kendall KR, Wang Y, Cheung A, Haigis MC, Glickman JN, Niwa-Kawakita M,  Sweet-Cordero A, Sebolt-Leopold J, Shannon KM, Settleman J, Giovannini M,  and  Jacks T.  (March 30, 2008) "Differential effects of oncogenic K-Ras and N-Ras on proliferation, differentiation and tumor progression in the colon".
Nature Genetics 40, 600 - 608 (2008). Published online: 30 March 2008 | doi:10.1038/ng.115).

12. Gordân R, Hartemink AJ, and Bulyk ML
"Distinguishing direct versus indirect transcription factor-DNA interactions".


13. Frenster JH, and Hovsepian JA,
"Models of successive levels of resolution during individual gene transcription".

14. 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".

15. 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".

16. Li L, Feng T, Lian Y, Zhang G, Garen A, and Song X, (2009).
"Role of human noncoding RNAs in the control of tumorigenesis".


17. Kim HH, Kuwano Y, Srikantan S, Lee EK, Martindale JL, and Gorospe M, (2009).
"HuR recruits let-7/RISC to repress c-Myc expression".

18. Kotani A, Ha D, Hsieh J, Rao PK, Schotte D, den Boer ML, Armstrong SA, and Lodish HF, (2009).
"miR-128b is a potent glucocorticoid sensitizer in MLL-AF4 acute lymphocytic leukemia cells and exerts cooperative effects with miR-221".

19. Thiery JP, Acloque H, Huang RYJ, and Nieto MA, (2009).
"Epithelial-Mesenchymal Transitions in Development and Disease".

20. 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".

21. Short B, (2009)
"Genes make their position clear".

22. 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".

23. Iorio MV, and Croce CM, (2009).
"MicroRNAs in Cancer: Small molecules with a huge impact".
J. Clin. Oncology, vol. 27: no. 34, pp. 5848-5856 (December 1, 2009).

24. Faber J, Gregory RI, and Armstrong SA, (2008).
"Linking miRNA Regulation to BCR-ABL Expression: The Next Dimension ",
Cancer Cell, vol. 13, no. 6, pp. 467-469 (June 10,  2008).

25. Nicodemi M, and Prisco A, (2009).
"Thermodynamic Pathways to Genome Spatial Organization in the Cell Nucleus".
Biophysical Journal vol. 96, issue 6, pp. 2168-2177 (March 18, 2009).

Figure 2: Thermodynamic switches for intrachromosomal contacts and loop formation.

Figure 2: Thermodynamic switches for intrachromosomal contacts and loop formation.

The equilibrium average gyration radius, Rg2, of the model polymer pictured in Fig.1, depends on the affinity, EX, of its binding sites for a set of molecular factors, on the concentration, c, of those factors, and on the fraction, f, of polymer beads which can bind molecules. Rg represents the radius of a sphere enclosing the polymer: it has a maximum (Rg2 = 1 in our normalization) when folding is random and a minimum when the polymer loops on itself in a lump (the horizontal red line is the radius of a compact sphere formed by the polymer). In the left panel, Rg2 is shown as a function of EX, for a given value of c and f (here c = 0.04%, f = 1/3). For EX below a threshold value, , Rg2 is 1 and the polymer is on average open. For EX > Etr, Rg2 collapses, as the polymer forms a looped territory. In the central panel, Rg2 is shown as a function of c, for a given EX and f (here EX = 4 kT, f = 1/3). In addition, in this case a threshold effect is observed (), although a broader crossover region exists where the level of folding can be tuned. The right panel shows the sharp threshold of Rg2 as a function of f (, here c = 0.04%, EX = 4 kT), illustrating that only in presence of multiple sites (i.e., above ftr) the polymer can be folded in loops.

Conclusions from Euchromatin Thermodynamic Pathways.

1. Pathways within cell genomes involve a flow of information.

2. Information can flow by direct contact or by third parties.

3. Direct contact within whole genomes is difficult to regulate.

4. DNA-DNA direct contects are influenced by agents.

5. Nuclear agents include hydrophilic ionic and hydrophobic conforming ligands.

6. Third parties within genomes involve RNAs and proteins.

7.  RNAs and proteins are easy to regulate or reverse.

8.  Information can be shared, lost, or transformed.

9.  Local information can be permanently lost during system entropy.

10. System information can be hidden during isolation.

December 8, 2009.
Up-dated:  http://www.embryomas.net#Conclusions02



Further Topics in:  Euchromatin,  active DNA, and  RNA  ribo-regulators:

Links to Current Research in Euchromatin:
Links to Euchromatin Activator RNA Reviews:
Links to Euchromatin Activator RNA Research:
Links to Ultrastructural Probes of DNase I-Sensitive Sites:
Links to RNA as a Therapeutic Agent:
Links to Hodgkin Lymphoma Immuno-Pathology:
Links to Activated T-Lymphocyte Immunotherapy:
Links to Medical Systems Biology:
Links to Selective Gene Transcription:
Links to RNA-Induced Epigenetics:
Links to RNA-Induced Embryogenesis:
Links to RNA and Biological Causality:
Links to Reprogramming and Neoplasia:

A Brief History of Activator RNA:

"Ultrastructural Probes of Active DNA Sites, and the RNA Activators of DNA".
(PowerPoint Presentation).

Top of Page - Euchromatin Network -  Euchromatin Research -  Research in Quantitative Radiology

For Further Information and Feedback:

Jeannette A. Hovsepian, M.D.
E-mail: frensasc@ix.netcom.com
Phone:  +1 650 367 6483


euchromatin: "the most active portion of the genome within the cell nucleus".
embryoma:  "adult neoplasm expressing one or more embryo-exclusive genes".