Thesis (Ph. D.)--Cornell University, January, 2009. / Vita. Includes bibliographical references.

Thesis (M. Phil.)--University of Hong Kong, 2008. / Includes bibliographical references (leaves 99-118) Also available in print.

Thesis (M. Phil.)--University of Hong Kong, 2008. / Includes bibliographical references (leaves 99-118) Also available online.

Thesis (Ph. D.)--University of Alabama at Birmingham, 2008. / Title from first page of PDF file (viewed Feb. 13, 2009). Includes bibliographical references.

Thesis (Ph.D.). / Written for the Dept. of Experimental Medicine. Title from title page of PDF (viewed 2009/06/09). Includes bibliographical references.

Thesis (Ph. D.)--University of Oklahoma. / Bibliography: leaves 190-220.

Thesis (Ph. D.)--University of Oregon, 2006. / Typescript. Includes vita and abstract. Includes bibliographical references (leaves 88-100). Also available for download via the World Wide Web; free to University of Oregon users.

Made available in DSpace on 2015-07-22T20:50:07Z (GMT). No. of bitstreams: 0 Previous issue date: 2011-06-29. Added 1 bitstream(s) on 2015-08-11T03:26:07Z : No. of bitstreams: 1 Publico-12659.pdf: 1883382 bytes, checksum: 33bb0f719078a000b15563f9e2debf90 (MD5) / A familia de genes Wnt esta envolvida na carcinogenese de diversos tecidos e na embriogenese. Para avaliar as vias Wnt canonica e nao-canonica no endometrio atrofico e no cancer de endometrio, avaliamos a expressao imuno-histoquimica do Wnt1, Frizzled-1 (FZD1), Wnt5a, Frizzled-5 (FZD5) e ƒÀ-catenina. O tecido endometrial foi retirado de pecas cirurgicas de pacientes operadas entre 1995 e 2005 na Escola Paulista de Medicina . UNIFESP e foram divididas em dois grupos: grupo A, endometrio atrofico (n=15) e grupo B, adenocarcinoma de endometrio (n=45). A imunorreacao do Wnt1, FZD1, Wnt5a, FZD5 and ƒÀ-catenina foi analisada em escores em cada grupo, individualmente. A expressao do Wnt1, FZD1 e Wnt5a nao teve associacao significante entre os grupos. Associacao significante foi observada entre os grupos para a expressao do FZD5 (p = 0,001). A proporcao do FZD5 positivo foi significativamente maior no grupo A (80,0%) comparado ao grupo B (31,1%). Analisando a curva de sobrevida para o FZD5 no grupo B, nao encontramos associacao significante entre as mulheres positivas e negativas. A expressao da scatenina nao foi significante, sendo a expressao para os grupos A e B 100% e 95.6%, respectivamente (p = 1,000). FZD5 tem menor expressao no adenocarcinoma de endometrio tipo I quando comparado ao endometrio atrofico. / The Wnt family is involved in tumorigenesis of several tissues as well in embriogenesis. In order to analize the canonical and noncanonical Wnt pathway in atrophic endometrium and endometrial adenocarcinoma, we evaluated the immunohistochemical expression of Wnt1, Frizzled-1 (FZD1), Wnt5a, Frizzled-5 (FZD5) and ƒÀ-catenin. Endometrial specimens were obtained from surgeries performed between 1995 and 2005 and the patients were divided in two groups: Group A, atrophic endometrium (N = 15); Group B, endometrial adenocarcinoma (N = 45). Immunoreactivity for Wnt1, FZD1, Wnt5a, FZD5 and ƒÀ-catenin was scored for each group. For the expression of Wnt1, FZD1 and Wnt5a, no significant association was observed between the groups. A significant association was observed between the groups for the FZD5 expression (p = 0.001). The proportion of FZD5 positive women was significantly higher for group A (80.0%) compared to group B (31.1%). Regarding the survival curve for FZD5 at group B, we found no significant association between positive and negative women. No significant association was observed between s-catenin expression and the patient group since the expression for groups A and B were 100% and 95.6%, respectively (p = 1.000). FZD5 is downregulated in type I endometrial adenocarcinoma when compared to atrophic endometrium. / TEDE / BV UNIFESP: Teses e dissertações

According to the cancer stem cells (CSCs) hypothesis, CSCs are responsible for the treatment failures. CSCs are a subset of cells possessing stemness properties within the heterogeneous tumor mass. Therapeutic intervention on Wnt signaling is of our great interest because an aberrant Wnt signaling is an important driver to maintain the potency of CSCs. In nasopharyngeal carcinoma (NPC), deregulated expression of the Wnt signaling components is frequently observed. ICG-001 is a selective Wnt modulator (CBP antagonist) that specifically interrupts the interaction between β-catenin and CBP, thereby encourages the interaction between β-catenin and p300 and the subsequent differentiation and reduction of the CSCs subset. For this reason, the present study aimed to evaluate the therapeutic potential of ICG-001 in NPC. Results showed that ICG-001 inhibited both the migration of the NPC cells and the formation of tumor spheres. In the first part of the mechanistic studies (Chapter 3), ICG-001 was found to restore the expression of miR-150 in NPC cells. MiR-150 was further found to directly reduce CD44 expression and inhibit NPC cell migration. In the second part of the mechanistic studies (Chapter 4), ICG-001 was found to reduce the expression of Evi1 in NPC cells. The effect was accompanied with the inhibition of both the NPC cells migration and the tumor spheres formation. Two molecular axes, namely miR-96/Evi1/miR-449a and survivin/Evi1/miR-449a, were found to be involved in the inhibition of the tumor cell migration and spheroids formation. The therapeutic potential of using this CBP antagonist (ICG-001) in NPC, namely the in vitro and in vivo efficacy of ICG-001 combined with cisplatin, was examined (Chapter 5). Concurrent treatment of ICG-001 and cisplatin exhibited a synergistic inhibition on the in vitro growth and the tumor sphere forming capacity of NPC cells as well as the growth of NPC xenografts. Taken together, results presented in this thesis suggested that ICG-001 (PRI-724 is the analog of ICG-001 currently used in clinical trials) has a therapeutic potential in NPC.

During regeneration, cells must coordinate proliferation and differentiation to rebuild tissues that are lost. Understanding how source cells execute the regeneration process has been a longstanding goal in regenerative biology with implications in wound healing and cell replacement therapies. Melanocytes are pigment-producing cells in the skin of vertebrates that can be lost during hair graying, injury and disease-related depigmentation. Melanoma is an aggressive skin cancer that develops from melanocytes, and it is hypothesized that melanoma cells have properties that are similar to melanocyte stem cells. To gain insight into melanocyte regeneration we set out to identify the source of regeneration melanocytes in adult zebrafish and the path through which progenitor cells reconstitute the pigment pattern. Using targeted cell ablation and single cell lineage-tracing analyses we identified that a majority of regeneration melanocytes arise through direct differentiation of mitfa-expressing progenitor cells. Concurrently, other mitfa-expressing cells divide symmetrically to generate additional mitfa-positive progenitors, thus maintaining regeneration capability. Using reporter assays and drug studies, we found that Wnt signaling gets turned on in progenitor cells during regeneration and Wnt inhibition after melanocyte ablation blocks regeneration. Based on our finding that Wnt signaling is active in differentiated melanocytes but not in the progenitor cells, we explored the role of Wnt signaling in tumor initiation. We found that approximately half of the melanomas are Wnt silent, and overexpression of dkk1b, a negative regulator of canonical Wnt signaling, accelerates melanoma onset. This work defines an unappreciated contribution by direct differentiation in melanocyte regeneration and suggests a broader role for this process in the maintenance of epithelial sheets. This study also identifies a shared pathway between melanocyte progenitors and melanoma cells, which could be applicable to other cancers.