Abstract SY02-02: Novel mechanisms regulating breast cancer progression, metastasis, and response to therapy
Authors: Zena Werb
Journal: Cancer Research (2010)

Abstract In 1863, Virchow hypothesized that the cancer originated at sites of chronic tissue injury and that the ensuing inflammation they cause enhances cell proliferation. While it is now clear that proliferation of cells alone does not cause cancer, sustained cell proliferation in an environment rich in inflammatory cells, growth factors, activated stroma and DNA damage promoting agents, certainly potentiates and/or promotes neoplastic risk. In fact, in some cases, the trigger for neoplastic progression may even come from signals within the stromal microenvironment. The stromal microenvironment consists of several cell types (fibroblasts, macrophages, vascular components, and inflammatory cells of the innate and acquired immune response), as well as the extracellular matrix that they elaborate and all the molecules that are concentrated and immobilized on it. All of these components communicate with each other and with the neoplastic cells to contribute to the aberrant tumor organ. We used genetic and imaging techniques to study the interaction between inflammatory and epithelial cancer cells during tumor progression. We visualized the behavior of the cancer cells and leukocytes in living, anaesthetized mice using a spinning disk confocal microscope. We found that leukocytes observed at the tumor-stroma interface are very motile whereas those within the tumor are relatively immotile. The inflammatory switch occurred in parallel with the malignant conversion of the tumor cells. Transcriptional regulation of epithelial differentiation, cell-cell interaction and motility was a key intrinsic event in tumor progression. Tumor cell progression was regulated by GATA3, a master regulator for luminal differentiation, which was lost upon malignant progression, when the tumor cells disseminated throughout the body. Restoration of GATA3 into the malignant cells prevented the earliest stage of tumor metastasis, tumor cell dissemination, and altered the stromal response including decreasing angiogenesis. Zeppo1, a transcriptional repressor present in an amplicon on human chromosome 8p12, regulated epithelial cell adhesion and migration, enhancing later events in metastasis. The inflammatory cells modulate the tumor ecology, altering vascular permeability and responses to chemotherapy. The dynamic interplay of tumor cells and host cells responding to the tumor contribute to tumor evolution and evasion of therapeutic responses.Our data support the hypothesis that that both extrinsic and intrinsic mechanisms regulate tumor progression. Egeblad, M., A. J. Ewald, et al. (2008). Visualizing stromal cell dynamics in different tumor microenvironments by spinning disk confocal microscopy. Dis. Model. Mech. 1:155-167. PMID: 1904807 Ewald, A.J., A. Brenot, M. Duong, B.S. Chan &amp; Z. Werb (2008). Collective epithelial migration and cell rearrangements drive mammary branching morphogenesis. Dev. Cell. 14:570-581. PMID: 18410732. Kouros-Mehr, H., S. K. Bechis, et al. (2008). GATA-3 links tumor differentiation and dissemination in a luminal breast cancer model. Cancer Cell. 13:141-52. PMID: 18242514. Lu, P. &amp; Z. Werb (2008). Patterning mechanisms of branched organs. Science. 322:1506-1509. PMID: 19056977. Welm, B.E, G. J. P. Dijkgraaf, A. S. Bledau, A. L. Welm &amp; Z. Werb (2008). Lentiviral transduction of stem cells for genetic analysis of mammary development and breast cancer. Cell Stem Cell. 2:90-102. PMID: 18371425. Citation Format: Zena Werb. Novel mechanisms regulating breast cancer progression, metastasis, and response to therapy [abstract]. In: Proceedings of the AACR 101st Annual Meeting 2010; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr SY02-02