“Models of Embryonic Gene-Induced Initiation and Reversion of Adult Neoplasms”.

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

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

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

Embryonic gene re-expression can initiate adult neoplasms within normal adult mouse fibroblasts (Okito K, Ichisaki I, and Yamanaka S, “Generation of germline-competent induced pluripotent stem cells”, Nature 448: 313-317, July19, 2007). As little as only one normal embryonic gene need be re-expressed for such an adult neoplastic initiation to occur. This constitutes a minimal gene dose. The molecular mechanism is believed to involve the disruption of a normal nuclear signal between normal adult genes within the normal adult cell.

Conversely, certain microRNAs (let-7 RNA) are deficient within the resected tumors of patients with NSCLC lung cancer (Takamizawa J, Konishi H, Yanagisawa K, Tomida S, Osada H, Endo H, Harano T, Yatabe Y, Nagino M, Nimura Y, Mitsudomi T, and Takahashi T, “Reduced Expression of the Let-7 MicroRNAs in Human Lung Cancers in Association with Shortened Postoperative Survival”, Cancer Research 64: 3753-3756 (2004). When adult human NSCLC cancer cells in cell culture are treated with let-7 RNA via plasmid, their rate of growth in cultures is reduced toward normal (ibid).

The molecular mechanism is believed to reflect the known inhibitory effect of let-7 RNA on RAS and other oncogenes during embryogenesis  (Johnson SM, Grosshans H, Shingara J, Byrom M, Jarvis R, Cheng A, Labourier E, Reinert KL, Brown D, and Slack FJ, “RAS is Regulated by the Let-7 MicroRNA Family”, Cell 120: 635-647 (2005). The transcriptome context within the cell nucleus during embryogenesis is quite different from that context within the cell nucleus of the same cells during adult life. Specific single gene expression in one phase of cell life may be inappropriate, or even dangerous, in another phase of cell life.

A simple hypothesis postulates that preventing such inappropriate embryonic gene re-expression may prevent initiation of adult neoplasms, while administration of specific embryonic ribo-regulators to adult neoplastic cells may be capable of reverting the neoplastic activity of such neoplasms.

Interestingly, it has already been shown that the administration of unfractionated total RNA from the bone marrow aspirates of normal human donors into the marrow or blood of adult patients with acute myelocytic leukemia in full relapse results in significant in-vivo reductions in the leukemic state within each patient (DeCarvalho S, “Effect of RNA from Normal Human Marrow on Leukemic Marrow In-Vivo”, Nature 197:  1077-1080 (March 16, 1963).

Adult neoplasms often re-express genes normally expressed only during embryogenesis. This ectopic re-appearance of RNA transcripts from these embryonic genes within normal adult cells may play a role in oncogenesis, metastases, and response to therapy of these adult cells.

For example, in the study of human non-small cell lung cancer (NSCLC), it has been observed that activity of the embryonic gene enhancer let-7  is often deficient, and that when let-7 is added back to such cancer cells in culture, the functional phenotype of the cancer cells is normalized, (Takamizawa J, Konishi H, Yanagisawa K, Tomida S, Osada H, Endoh H, Harano T, Yatabe Y, Nagino M, Nimura Y, Mitsudomi T,  and Takahashi T, “Reduced expression of the let-7 microRNAs in human lung cancers in association with shortened postoperative survival”, Cancer Res. 64: 3753–3756, 2004).

let-7 is an active locus in promoting cell differentition and maturation in embryonic cells, and is particularly important in controlling the activity of ras genes during embryogenesis, (Johnson SM, Grosshans H, Shingara J, Byrom M, Jarvis R, Cheng A, Labourier E, Reinert KL, Brown D, and Slack FJ, “RAS is regulated by the let-7 microRNA family”, Cell 120: 635–647, 2005).

It has now been shown that let-7 RNA binds to known embryonic oncogenes, and by such binding, inactivates such oncogenes within adult cells, (Mayr C, Hemann MT, and Bartel DP, "Disrupting the Pairing Between let-7 and Hmga2 Enhances Oncogenic Transformation", Science, 315: 1576-1579, 2007).

A simple hypothesis postulates that specific embryonic cell RNA enhancers can have either positive or negative effects on their target embryonic genes within specific adult cells, progressively disrupting the adult gene signaling systems.  This allows oncogenesis to initiate from as little as one normal embryonic gene abnormally re-expressing itself within one adult normal cell.

5. Takamizawa J, Konishi H, Yanagisawa K, Tomida S, Osada H, Endoh H, Harano T, Yatabe Y, Nagino M, Nimura Y, Mitsudomi T,  and Takahashi T, “Reduced expression of the let-7 microRNAs in human lung cancers in association with shortened postoperative survival”, Cancer Research 64: 3753-3756 (2004).

6. Johnson SM, Grosshans H, Shingara J, Byrom M, Jarvis R, Cheng A, Labourier E, Reinert KL, Brown D, and Slack FJ, “RAS is regulated by the let-7 microRNA family”, Cell 120: 635-647 (2005).

7. Mayr C, Hemann MT, and Bartel DP, "Disrupting the Pairing Between let-7 and Hmga2 Enhances Oncogenic Transformation", Science, 315: 1576-1579 (2007).

8. Okita, K, Ichisaka T, and Yamanaka S, "Generation of germline-competent induced pluripotent stem cells",
Nature 448: 313-317 (July19, 2007).

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

Table 1: Interactions of sense and antisense RNAs within active euchromatin.
 

11. DeCarvalho S, “Effect of RNA from Normal Human Marrow on Leukemic Marrow In-Vivo”, Nature 197:  1077-1080 (March 16, 1963.

12. Meisner LF, and Frenster JH, "In-Vivo Evolution within Radiation-Induced Clones of Human Lymphocytes", J. Cell Biol. vol. 39, part 2, p. 155a (1968).

13. Herstein PR, and Frenster JH, "Mated Models of Gene Regulation in Eukaryotes", "Embryonic and Fetal Antigens in Cancer", vol. 2,  pp. 5-7, (Anderson NG, Coggin JH, eds.), National Technical Information Service, U.S. Dept. Commerce, Springfield, VA., 1972.

14. Frenster JH, and Herstein PR, "Gene De-Repression".

15. Frenster JH, and Hovsepian JA, "DNA-DNA Tetraplex Model of Paired Sense-Antisense RNA Synthesis".

16. Frenster JH, and Hovsepian JA, "DNase-I Ultrastructural Probe Sites and Kissing Chromosomes".

1. Embryonic genes are those normally expressed only during embryonic life.

2. These embryonic RNA enhancers and activators are most often not expressed within normal adult human cells.

3. The re-expression of normal embryonic genes within an adult normal cell carries the risk of initiating a neoplasm within the adult normal cell.

4. Some adult lung neoplasms express a deficiency of let-7 microRNA, with the more severe deficiency of let-7 microRNA correlating with a decreased patient survival after resection of the neoplasm.

5. Addition of let-7 microRNA via plasmid to such lung neoplastic cells in culture results in decreased growth of these cells.

6. Total unfractionated RNA from normal bone marrow donors can produce brief clinical remissions when given to relapsed patients with acute myelocytic leukemia.

1. Any embryonic gene is a potential oncogene, and is capable of initiating a neoplasm when it is re-expressed within an adult normal cell.

2. Embryonic gene ribo-regulator RNAs may reverse the action of such re-expressed embryonic genes.

3. Embryonic gene re-expression within normal adult cells is a final common RNA pathway for most, if not all, human neoplasms.

4. Ribo-regulator RNA therapy may be effective in reversing the neoplastic activity within neoplastic cells already damaged by chromosomal translocations, inversions, deletions, duplications or viral integrations.

5. Systems for the delivery of embryonic ribo-regulator RNAs can be developed for the therapy of adult neoplasms.

6. Ribo-regulator RNAs can be a focus of cancer therapy and of cancer prevention.

Some genes within adult cells are normally expressed only during adult life.
Some genes within adult cells are normally expressed only during embryologic or fetal life.
Some genes within adult cells are normally expressed during both adult life and embryologic or fetal life.
Some genes within adult cells are not normally expressed, except during heat-shock or cold-shock.

Adult-only genes usually cannot express themselves during embryonic life.
Mixed embryo-adult genes are expressed during both embryonic life and adult life.
Embryo-only genes can be re-expressed ectopically within adult cells.

The re-expression of embryonic genes within adult cells may occur in the absence of embryonic controls.
The re-expression of embryonic genes in adult cells may initiate or revert neoplasms in the adult cells.
Each re-expression of embryonic genes within adult cells is a case unto itself.
Any embryonic gene-initiated neoplasms may have quite diverse transcription patterns.

1. Re-expression of embryonic genes within adult neoplasms now provide RNA and protein targets for effective therapy of human neoplasms.

(Wang J, Day R, Dong Y, Weintraub SJ, and Michel L,
"Identification of Trop-2 as an Oncogene and an Attractive Therapeutic Target in Colon Cancers",
Molec. Cancer Therap. 7: 280-285 (February 1, 2008).)

2. Re-expression of embryonic genes within adult neoplasms results in early invasive metastases.

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

3. Re-expression of embryonic RNA ribo-regulator let-7 microRNA suppresses human lung cancer cells.

(Kumar MS, Erkeland SJ, Pester RE, Chen CY, Ebert MS, Sharp PA, and Jacks T,
"Suppression of non-small cell lung tumor development by the let-7 microRNA family",
Proc. Natl. Acad. Sci. USA, vol. 105, no. 10 pp. 3903-3908 (March 11, 2008).)

4. Oncogenes may compete and/or cooperate during initiation of adult neoplasms.

(Podsypanina K, Politi K, Beverly LJ, and Varmus HE,
"Oncogene cooperation in tumor maintenance and tumor recurrence in mouse mammary tumors induced by Myc and mutant Kras",
Proc. Natl. Acad. Sci. U.S.A, 2008 Apr 1;105(13):5242-7. Epub 2008 Mar 20.)

5. Embryonic RNA controls self renewal and tumor activity in breast neoplasms.

(Yu F, Yao H, Zhu P, Zhang X, Pan Q, Gong C, Huang Y, Hu X, Su F, Lieberman J, and Song E.,
"let-7 regulates self renewal and tumorigenicity of breast cancer cells",
Cell. 2007 Dec 14;131(6):1109-23.)

6. Noncoding RNA genes are ultraconserved and altered within human neoplasms.

(Calin GA, Liu C-G, Ferracin M, Hyslop T, Spizzo R, Sevignani C, Fabbri M, Cimmino A, Lee EJ, Wojcik SE, Shimizu M, Tili E, Rossi S, Taccioli C, Pichiorri F, Liu X, Zupo S, Herlea V, Gramantieri L, Lanza G, Alder H, Rassenti L, Volinia S, Schmittgen TD, Kipps TJ, Negrini M, and Croce CM,
"Ultraconserved Regions Encoding ncRNAs Are Altered in Human Leukemias and Carcinomas",
Cancer Cell, Vol 12, 215-229, 11 September 2007.)

7. Embryonic RNA can distinguish between different types of neoplastic differentiation.

(Shell S, Park S-M, Radjabi AR, Schickel R, Kistner EO, Jewell DA, Feig C, Lengyel E, and Peter ME,
"Let-7 expression defines two differentiation stages of cancer",
Proc. Natl. Acad. Sci. U.S.A., vol. 104, no. 27, pp. 11400-11405  (July 3, 2007).

8. Embryonic stem-cell program is active within diverse human epithelial neoplasms.

(Wong DJ, Liu H, Ridky TW, Cassarino D, Segal E, and Chang HY,
"Module Map of Stem Cell Genes Guides Creation of Epithelial Cancer Stem Cells",
Cell Stem Cell, Vol 2, 333-344, 10 April 2008.)

9. Embryonic stem cell genes are active within adult human cervical cancer cells, but less so within normal, mildly dysplastic, or moderately dysplastic adult cervical cells, in patient biopsies.

(Ye F, Zhou C, Cheng Q, Shen J,  and Chen H,
"Stem cell abundant protein Nanog, Nucleostemin and Musashi1 highly expressed in malignant cervical epithelial cells",
BMC Cancer April 18, 2008, 8:108, doi:10.1186/1471-2407-8-108.)

10. Embryonic stem cells display many new and varied microRNAs.

(Morin RD, O’Connor MD, Griffith M, Kuchenbauer F, Delaney A, Prabhu A-L, Zhao Y, McDonald H, Zeng T, Hirst M, Eaves CJ, and Marra MA,
"Application of massively parallel sequencing to microRNA profiling and discovery in human embryonic stem cells",
Genome Res. vol. 18: no. 4, pp. 610-621 (April, 2008).

11. 3D atlas of fly embryonic gene expression.

(FowlkesCC, Luengo Hendriks CL, Keränen SVE, Weber GH, Rübel O, Huang M-Y, Chatoor S, DePace AH, Simirenko L, Henriquez C, Beaton A, Weiszmann R, Celniker S, Hamann B, Knowles DW, Biggin MD, Eisen MB,, and Malik J,
"A Quantitative Spatiotemporal Atlas of Gene Expression in the Drosophila Blastoderm",
Cell, Vol 133, 364-374, 18 April 2008).

12. Embryonic let-7 RNA regulates multiple oncofetal genes re-expressed in adult cancer cells.

(Boyerinas B, Park S-M, Shomron N, Hedegaard MM, Vinther J, Andersen JS, Feig C, Xu J,  Burge CB, and Peter ME,
"Identification of Let-7–Regulated Oncofetal Genes",
Cancer Research 68, 2587-2591, April 15, 2008.)

13. Embryonic gene re-expression found within invasive de-diifferentiated adult human neoplasms.

(Ben-Porath I, Thomson MW, Carey VJ, Ge R, Bell GW, Regev A,  and Weinberg RA,
"An embryonic stem cell–like gene expression signature in poorly differentiated aggressive human tumors".
Nature Genetics 40, 499 - 507 (2008). Published online: 28 April 2008 | doi:10.1038/ng.127)

14. Novel pathways for embryonic gene re-expression and initiation of adult colonic neoplasms.

(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.
"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)

15. MicroRNAs of the noncoding variety are involved in gene regulation of hematological neoplasms.

(Fabbri M, Garzon R, Andreeff M, Kantarjian HM, Garcia-Manero G, and Calin GA,
"MicroRNAs and noncoding RNAs in hematological malignancies: molecular, clinical and therapeutic implications",
Leukemia advance online publication 6 March 2008; doi: 10.1038/leu.2008.30)

16. Noncoding microRNAs 181a and 181b suppress the leukemic state in acute myelogenous leukemia.

(Marcucci G, Radmacher MD, Maharry K, Mrózek K, Ruppert AS, Paschka P, Vukosavljevic T, Whitman SP, Baldus CD, Langer C, Liu C-G, Carroll AJ, Powell BL, Garzon R, Croce CM, Kolitz JE, Caligiuri MA, Larson RA, and Bloomfield CD,
"MicroRNA Expression in Cytogenetically Normal Acute Myeloid Leukemia",
New England Journal of Medicine vol. 358: no. 18, pp. 1919-1928 May 1, 2008.)

17. Nanoparticles with 3 types of small interfering RNAs penetrate and silence oncogenes in vivo.

(Li S-D, Chono S, and Huang L,
"Efficient Oncogene Silencing and Metastasis Inhibition via Systemic Delivery of siRNA",
Molecular Therapy vol. 16, no.  5, pp. 942–946 (May, 2008).)

18. Selective microRNAs promote human neoplastic invasion and metastases in vitro and in vivo.

(Huang Q, Gumireddy K, Schrier M, le Sage C, Nagel R, Nair S, Egan DA, Li A, Huang G, Klein-Szanto AJ, Gimotty PA, Katsaros D, Coukos G, Zhang L, Puré E, and Agami R,
"The microRNAs miR-373 and miR-520c promote tumour invasion and metastasis",
Nature Cell Biology vol. 10, no. 2, pp. 202 - 210 (February, 2008).)

19. miR-200 and miR-205 are reduced during EMT within invasive breast cancer cells.

(Gregory PA, Bert AG, Paterson EL, Barry SC, Tsykin A, Farshid G, Vadas MA, Khew-Goodall Y, and Goodall GJ,
"The miR-200 family and miR-205 regulate epithelial to mesenchymal transition by targeting ZEB1 and SIP1",
Nature Cell Biology vol. 10, no. 5, pp. 593 - 601 (May, 2008).)

20. Oncosomes are exchanged between glioma cells for EGFRvIII activation of adjacent cells.

(Al-Nedawi K, Meehan B, Micallef J, Lhotak V, May L, Guha A, and Rak J,
"Intercellular transfer of the oncogenic receptor EGFRvIII by microvesicles derived from tumour cells",
Nature Cell Biology vol. 10, no. 5, pp. 619 - 624 (May, 2008).)

21. Mutually-dependent transcription factors increase oncogenesis.

(Li J,  and Wang C-Y,
"TBL1–TBLR1 and -catenin recruit each other to Wnt target-gene promoter for transcription activation and oncogenesis",
Nature Cell Biology vol. 10, no. 2, pp. 160 - 169 (February, 2008).)

22. Epithelial-mesenchymal interactions shape adult fibroblasts for positional memory.

(Rinn JL, Wang JK, Allen N, Brugmann SA, Mikels AJ, Liu H, Ridky TW, Stadler HS, Nusse R, Helms JA, and Chang HY,
"A dermal HOX transcriptional program regulates site-specific epidermal fate",
Genes & Development vol.  22: No. 3, pp. 303-307 (February,  2008). )

23. Long  noncoding RNAs regulate gene transcription in Human HOX loci.

(Rinn JL, Kertesz M, Wang JK, Squazzo SL, Xu X, Brugmann SA, Goodnough LH, Helms JA, Farnham PJ, Segal E, and Chang HY,
"Functional Demarcation of Active and Silent Chromatin Domains in Human HOX Loci by Noncoding RNAs",
Cell, vol 129, pp. 1311-1323 (June 29, 2007).)

24. Embryonic epithelial-mesenchymal transition generates stem-like cells.

(Mani SA, Guo W, Liao M-J, Eaton EN, Ayyanan A, Zhou AY, Brooks M, Reinhard F,  Zhang CC, Shipitsin M, Campbell LL, Polyak K, Brisken C, Yang J, and Weinberg RA,
"The Epithelial-Mesenchymal Transition Generates Cells with Properties of Stem Cells".
Cell, vol: 133, pp. 704-715 (May 16,  2008).)

25. Embryonic EMT (Ectodermal-Mesenchymal Transition) occurs in early cranial neural folds.

(Breau MA, Pietri T, Stemmler MP, Thiery JP, and Weston JA,
"A nonneural epithelial domain of embryonic cranial neural folds gives rise to ectomesenchyme",
Published online on May 30, 2008, Proc. Natl. Acad. Sci. USA, 10.1073/pnas.0711344105
http://www.pnas.org/cgi/content/abstract/0711344105v1?etoc.)

26. Embryonic Let-7 noncoding RNA neoplastic state of adult neoplastic cells.

(Boyerinas B, Park S-M, Shomron N, Hedegaard MM, Vinther J, Andersen JS, Feig C, Xu J,  Burge CB, and Peter ME,
"Identification of Let-7–Regulated Oncofetal Genes",
Cancer Research vol. 68, no. 8, pp. 2587-2591  (April 15, 2008).)

27. The c-myc oncogene functions as a required normal embryonic gene.

(He C, Hu H, Braren R, Fong S-Y, Trumpp A, Carlson TR, and Wang RA,
"c-myc in the hematopoietic lineage is crucial for its angiogenic function in the mouse embryo",
Development vol. 135, no. 14, pp. 2467-2477 (June, 2008).)

28. MicroRNA-203 suppresses ABL1 and BCR-ABL1 Oncogene expression.

(Bueno MJ, de Castro IP, de Cedrón MG, Santos J, Calin GA, Cigudosa JC, Croce CM, Fernández-Piqueras J and Malumbres M,
"Genetic and Epigenetic Silencing of MicroRNA-203 Enhances ABL1 and BCR-ABL1 Oncogene Expression",
Cancer Cell, vol. 13, no. 6, pp. 496-506 (June 10, 2008).)

29. RNA therapy may reverse the oncogenicity of fused proteins.

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

30. Adult neoplasms can become addicted to normal gene products.

(Shaffer AL, Tolga Emre NC, Lamy L, Ngo VN, Wright G, Xiao W, Powell J, Dave S, Yu X, Zhao H,  Zeng Y, Chen B, Epstein J, and Staudt LM,
"IRF4 addiction in multiple myeloma".
Nature vol. 454, no. 7201, pp. 226-231 (July 10, 2008)
http://www.nature.com/nature/journal/v454/n7201/abs/nature07064.html.)

31. Both oncogenes and normal genes can mediate the development and progress of cancer.

(Shaughnessy JD,
"Cancer: An unexpected addiction".
Nature vol.454, no. 7201, pp. 172-173 (July 10, 2008)
http://www.nature.com/nature/journal/v454/n7201/full/454172a.html.)

32. RNA inhibition of transcription factors can facilitate reprogramming.

(Mikkelsen TS, Hanna J, Zhang X, Ku M, Wernig M, Schorderet P, Bernstein BE, Jaenisch R,  Lander ES,  and  Meissner A,
"Dissecting direct reprogramming through integrative genomic analysis",
Nature vol. 454, no. 7200, pp. 49-55 (July 3. 2008) | doi:10.1038/nature07056;
http://www.nature.com/nature/journal/v454/n7200/abs/nature07056.html.)

33. Model for predictions about mechanisms of translocations within adult neoplastic cells.

(Soutoglou E, and Misteli T,
"On the Contribution of Spatial Genome Organization to Cancerous Chromosome Translocations",
JNCI Monographs 2008 2008(39):16-19; doi:10.1093/jncimonographs/lgn017;
http://jncimono.oxfordjournals.org/cgi/content/abstract/2008/39/16.)

34. Quantitative 3D spatial  analysis of neoplastic chromosomes.

(Grasser F, Neusser M, Fiegler H, Thormeyer T, Cremer M, Carter NP, Cremer T, and Müller S,
"Replication-timing-correlated spatial chromatin arrangements in cancer and in primate interphase nuclei".
J Cell Sci. 2008 Jun 1;121(Pt 11):1876-86. Epub 2008 May 13.
http://jcs.biologists.org/cgi/content/abstract/121/11/1876.)
 

35. Embryonic noncoding RNAs mediate oncogenesis within adult cells.

(Frenster JH, and Hovsepian JA, "Models of  Embryonic RNA Initiating and Reverting Adult Neoplasms". Section 6 (Cancer Genetics) of the XX International Congress of Genetics, "Understanding Living Systems", Berlin, Germany, July 12-17, 2008.)

36. Mechanisms of action of the oncogenic miR-17-92 MicroRNA cluster in adult ling cancer cells.

(Taguchi A, Yanagisawa K, Tanaka M, Cao K, Matsuyama Y, Goto H, and Takahashi T,
"Identification of Hypoxia-Inducible Factor-1a as a Novel Target for miR-17-92 MicroRNA Cluster",
Cancer Research vol. 68, pp. 5540-5545, (July 15, 2008).
http://cancerres.aacrjournals.org/cgi/content/abstract/68/14/5540.)

37. Pluripotent embryonic stem cells display global transcription signatures before cell differentiation.

(Efroni S, Duttagupta R, Cheng J, Dehghani JH, Daniel J. Hoeppner DJ, Chandravanu Dash C,  Bazett-Jones DP, Le Grice S, McKay RDG, Buetow KH, Gingeras TR, Misteli T, and Meshorer E,
"Global Transcription in Pluripotent Embryonic Stem Cells",
Cell Stem Cell, vol. 2, pp, 437-447, (08 May 2008).
http://www.cellstemcell.com/content/article/abstract?uid=PIIS1934590908001616.)

38. Integrin a1b1 acts as a co-oncogene for Kras in inducing NSCLC lung cancer.

(Macias-Perez I, Borza C, Chen X, Yan X, Ibanez R, Mernaugh G, Matrisian LM, Zent R, and Pozzi A,
"Loss of Integrin a1b1 Ameliorates Kras-Induced Lung Cancer",
Cancer Research vol. 68, pp. 6127-6135, (August 1, 2008).
http://cancerres.aacrjournals.org/cgi/content/abstract/68/15/6127.)

39. Short hairpin RNA targeting c-FLIP sensitizes human cervical adenocarcinoma Hela cells".

Luoa A, Wanga W, Simaa N, Lua Y, Zhoua J, Xua G, Yub H, Wanga S, and Ma D,
"Short hairpin RNA targeting c-FLIP sensitizes human cervical adenocarcinoma Hela cells to chemotherapy and radiotherapy",
Cancer Letters: doi:10.1016/j.canlet.2008.06.026

40. MicroRNA let-7b is down-regulated in primary malignant melanoma, and restores a benign phenotype.

(Schultz J, Lorenz P, Gross G, Ibrahim S, and Kunz M,
"MicroRNA let-7b targets important cell cycle molecules in malignant melanoma cells and interferes with anchorage-independent growth",
Cell Research vol. 18, no. 5, pp. 549–557 (May, 2008).
doi: 10.1038/cr.2008.45; published online 1 April 2008
http://www.nature.com/cr/journal/v18/n5/abs/cr200845a.html.)

41. High-resolution cell lineage and gene  expression traced through embryogenesis.

(Murray JI, Bao Z, Boyle TJ, Boeck ME, Mericle BL, Nicholas TJ, Zhao Z, Sandel MJ, and Waterston RH,
"Automated analysis of embryonic gene expression with cellular resolution in C. elegans",
Nature Methods - vol. 5; no. 8, pp. 703 - 709 (August, 2008)
Published online: 29 June 2008; | doi:10.1038/nmeth.1228
http://www.nature.com/nmeth/journal/v5/n8/abs/nmeth.1228.html.)

42. Key embryonic stem cell transcription factors promote the ES cell miRNA expression program.

(Marson A, Levine SS, Cole MF, Frampton GM, Brambrink T, Johnstone S, Guenther MG, Johnston WK, Wernig M, Newman J, Calabrese JM, Dennis LM, Volkert TL, Gupta S, Love J, Hannett N, Sharp PA, Bartel DP, Jaenisch R, and Young RA,
"Connecting microRNA Genes to the Core Transcriptional Regulatory Circuitry of Embryonic Stem Cells",
Cell, vol. 134, no. 3, pp. 521-533 (August 3, 2008). doi:10.1016/j.cell.2008.07.020
 

43. Mouse ES cell extracts rapidly induce pluripotency genes of human somatic cells.

(Bru T, Clarke C, McGrew MJ, Sang HM, Wilmut I, and Blow JJ,
"Rapid induction of pluripotency genes after exposure of human somatic cells to mouse ES cell extracts ",
Experimental Cell Research, vol. 314, no. 14, pp. 2634-2642 (August 15, 2008).)   doi:10.1016/j.yexcr.2008.05.009

44.   Canonical  embryonic oncogenic development of Basal Cell Carcinomas.

(Yang SH, Andl T, Grachtchouk V, Wang A, Liu J, Syu L-J, Ferris J, Wang TS, Glick AB, Millar SE,  and Dlugosz AA,
"Pathological responses to oncogenic Hedgehog signaling in skin are dependent on canonical Wnt/bold beta-catenin signaling",
Nature Genetics vol. 40, no. 9, pp. 1130 - 1135 (September, 2008) ;
Published online: 1 August 2008 | doi:10.1038/ng.192
http://www.nature.com/ng/journal/v40/n9/abs/ng.192.html.)

45. Multi-lineage differentiation and replication from colon cancer stem cells.

(Vermeulen L, Todaro M, de Sousa Mello, Sprick FMR, Kemper K, Perez Alea M, Richel DJ, Stassi G, and Medema JP.
"Single-cell cloning of colon cancer stem cells reveals a multi-lineage differentiation capacity".
PNAS September 9, 2008 vol. 105 no. 36 13427-13432
http://www.pnas.org/content/105/36/13427.abstract?etoc.)

46. Untransformed mammary cells may establish residence in the lung once they have entered the bloodstream and may assume malignant growth upon oncogene activation.

(Podsypanina K, Du Y-CN, Jechlinger M, Beverly LJ, Hambardzumyan D, and Varmus H,
"Seeding and Propagation of Untransformed Mouse Mammary Cells in the Lung",
Science 26 September 2008: Vol. 321. no. 5897, pp. 1841 - 1844 DOI: 10.1126/science.1161621
http://www.sciencemag.org/cgi/content/short/321/5897/1841.)

47. Inflammation-like state accelerates the migration of primary tumour cells to lung tissues.

(Hiratsuka S, Watanabe A, Sakurai Y, Akashi-Takamura S, Ishibashi S, Miyake K, Shibuya M, Akira S, Aburatani H,  and  Maru Y,
"The S100A8–serum amyloid A3–TLR4 paracrine cascade establishes a pre-metastatic phase",
Nature Cell Biology, Published online: 28 September 2008 | doi:10.1038/ncb1794
http://www.nature.com/ncb/journal/vaop/ncurrent/abs/ncb1794.html.)

48. Murine leukemia progression and expression of multiple miRNAs.

(Kuchenbauer F, Morin RD, Argiropoulos B, Petriv OI, Griffith M, Heuser M, Yung E, Piper J, Delaney A, Prabhu A-L, Zhao Y, McDonald H, Zeng T, Hirst M, Hansen CL, Marra MA, and  Humphries RK,
"In-depth characterization of the microRNA transcriptome in a leukemia progression model".,
Published online before print October 10, 2008, Genome Research, DOI: 10.1101/gr.077578.108)

49. Reprogramming of human cancer cells by microRNA.

 (Lin S-L, Chang DC, Chang-Lin S, Lin C-H, Wu DTS, Chen DT, and Ying S-Y,
"Mir-302 reprograms human skin cancer cells into a pluripotent ES-cell-like state".
RNA vol. 14: no. 10, pp. 2115-2124 (October, 2008).

50. Embryonic let-7 microRNA complementary site SNP in KRAS 3' UTR increases Non-Small Cell Lung Cancer risk".

(Chin LJ, Ratner E, Leng S, Zhai R, Nallur S, Babar I, Muller R-U, Straka E, Su L, Burki EA, Crowell RE, Patel R, Kulkarni T, Homer R, Zelterman D, Kidd KK, Zhu Y, Christiani DC, Belinsky SA, Slack FJ, and Weidhaas JB,
"A SNP in a let-7 microRNA complementary  site in the KRAS 3' Untranslated Region increases Non–Small Cell Lung Cancer risk",
Cancer Research 68, 8535-8540, October 15, 2008. doi: 10.1158/0008-5472.CAN-08-2129.)

51. Multiple non-uniform asynchronous chromosomal changes during neoplastic progression.

(Li X, Galipeau PC, Sanchez CA, Blount PL, Maley CC,  Arnaudo J, PeifferDA, Pokholok D, Gunderson KL, and Reid BJ,
"Single Nucleotide Polymorphism–Based Genome-Wide Chromosome Copy Change, Loss of Heterozygosity, and Aneuploidy in Barrett's Esophagus Neoplastic Progression",
Cancer Prevention Research 1, 413-423, November 1, 2008. doi: 10.1158/1940-6207.CAPR-08-0121)
http://cancerpreventionresearch.aacrjournals.org/cgi/content/abstract/1/6/413?..)

52. Short RNA GAS1 suppresses metastases within human melanoma cell lines.

(Gobeil S, Zhu X, Doillon CJ, and Green MR,
"A genome-wide shRNA screen identifies GAS1 as a novel melanoma metastasis suppressor gene",
Genes & Development. vol.22: no. 21, pp. 2932-2940, (November 1, 2008).
http://genesdev.cshlp.org/content/22/21/2932.abstract ).

53. Decrease in DNA copy-number is found within numerous human neoplasms.

(Varambally S, Cao Q, Mani R-S, Shankar S, Wang  X, Ateeq  B, Laxman  B, Cao X,  Jing  X, Ramnarayanan  K, J. Brenner JC, Yu J, Kim JH, Han B, Tan P, Kumar-Sinha C , Lonigro RJ, Palanisamy  N, Maher CA, Chinnaiyan AM,
"Genomic Loss of microRNA-101 Leads to Overexpression of Histone Methyltransferase EZH2 in Cancer",
 Published Online November 13, 2008 Science DOI: 10.1126/science.1165395).)

54. Heat Shock protein reacts with Ras oncogene in neoplastic epithelial cells.

(Gabai VL, Yaglom JA, Waldman T, and Sherman MY,
"Heat Shock Protein Hsp72 Controls Oncogene-Induced Senescence Pathways in Cancer Cells"
Molecular and Cellular Biology, January 2009, p. 559-569, Vol. 29, No.2 ).

55. Proto-oncogene interferes with normal differentiation.

(Wise-Draper TM, Morreale RJ, Morris TA, Mintz-Cole RA, Hoskins EE, Balsitis SJ, Husseinzadeh N, Witte DP, Wikenheiser-Brokamp KA, Lambert PF  and Wells SI,
"DEK Proto-Oncogene Expression Interferes with the Normal Epithelial Differentiation Program",
Published online before print November 26, 2008 (American Journal of Pathology. 2009;174:71-81.)
http://www.jbc.org/cgi/content/abstract/284/2/1018?.)

56. Embryologic EMT genes activated in prostatic carcinoma.

(Shah GV, Muralidharan A, Gokulgandhi M, Soan K, and Thomas S,
"Cadherin Switching and Activation of b-Catenin Signaling Underlie Proinvasive Actions of Calcitonin-Calcitonin Receptor Axis in Prostate Cancer",
J. Biol. Chem., Vol. 284, Issue 2, 1018-1030, January 9, 2009.)

Eastham AM, Spencer H, Soncin F, Ritson S, Merry CLR, Stern PL, and Ward CM,
"Epithelial-Mesenchymal Transition Events during Human Embryonic Stem Cell Differentiation",
Cancer Research 67, 11254-11262, December 1, 2007.

Links to Reprogramming and Neoplasia:

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A Brief History of Activator RNA:

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