Bcl3 is a putative proto-oncogene deregulated in hematopoietic and solid tumors. Studies in cell lines suggest that its oncogenic effects are mediated through the induction of proliferation and inhibition of cell death, yet its role in endogenous solid tumors has not been established. Here, we address the oncogenic effect of Bcl3 in vivo and describe how this Stat3-responsive oncogene promotes metastasis of ErbB2-positive mammary tumors without affecting primary tumor growth or normal mammary function. Deletion of the Bcl3 gene in ErbB2-positive (MMTV-Neu) mice resulted in a 75% reduction in metastatic tumor burden in the lungs with a 3.6-fold decrease in cell turnover index in these secondary lesions with no significant effect on primary mammary tumor growth, cyclin D1 levels, or caspase-3 activity. Direct inhibition of Bcl3 by siRNA in a transplantation model of an Erbb2-positive mammary tumor cell line confirmed the effect of Bcl3 in malignancy, suggesting that the effect of Bcl3 was intrinsic to the tumor cells. Bcl3 knockdown resulted in a 61% decrease in tumor cell motility and a concomitant increase in the cell migration inhibitors Nme1, Nme2, and Nme3, the GDP dissociation inhibitor Arhgdib, and the metalloprotease inhibitors Timp1 and Timp2. Independent knockdown of Nme1, Nme2, and Arhgdib partially rescued the Bcl3 motility phenotype. These results indicate for the first time a cell-autonomous disease-modifying role for Bcl3 in vivo, affecting metastatic disease progression rather than primary tumor growth. Cancer Res; 73(2); 745-55. Ó2012 AACR.

Cancerous tumours contain a rare subset of cells with stem-like properties that are termed cancer stem cells (CSCs). CSCs are defined by their ability to divide both symmetrically and asymmetrically, to initiate new tumour growth and to tolerate the foreign niches required for metastatic dissemination. Accumulating evidence suggests that tumours arise from cells with stem-like properties, the generation of CSCs is therefore likely to be an initiatory event in carcinogenesis. Furthermore, CSCs in established tumours exist in a dynamic and plastic state, with nonstem tumour cells thought to be capable of de-differentiation to CSCs. The regulation of the CSC state both during tumour initiation and within established tumours is a desirable therapeutic target and is mediated by epigenetic factors. In this review, we will explore the epigenetic parallels between induced pluripotency and the generation of CSCs, and discuss how the epigenetic regulation of CSCs opens up novel opportunities for therapeutic intervention. K E Y W O R D S cancer stem cells, cancer therapy, early detection of cancer, epigenetics, induced pluripotent stem cells, tumorigenesis 1 | INTRODUCTION As with adult tissues, cancerous tumours also contain a rare subset of cells with stem-like properties that can function to regenerate the heterogeneous cell populations observed therein. These cancer stem cells (CSCs) are defined by their ability to divide both symmetrically and asymmetrically, to initiate new tumour growth and to tolerate the foreign niches required for metastatic dissemination. As the tumourinitiating population, CSCs underpin the very nature of malignancy and studying their regulation is essential for understanding tumour formation, metastasis and relapse after therapy. As it is not possible to isolate CSCs based on functional properties, CSC identification can be achieved by FACs sorting based on surrogate cell surface marker profiles and subsequent transplantation into immune-compromised mice to demonstrate enhanced tumourigenic potential. Using this strategy, CSCs have been identified in most cancers, first in acute myeloid leukaemia (AML) followed by breast cancer and other solid malignancies such as brain, colon and pancreatic cancer, and are purported to account for only a few per cent of the total cell population.

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The nature of the tumor microenvironment (TME) influences the ability of tumorspecific T cells to control tumor growth. In this study we performed an unbiased comparison of the TME of Treg-replete and Treg-depleted carcinogen-induced tumors, including Treg-depleted responding (regressing) and non-responding (growing) tumors. This analysis revealed an inverse relationship between extracellular matrix (ECM) and T cell infiltrates where responding tumors were T cell rich and ECM poor whereas the converse was observed in non-responder tumors. For this reason, we hypothesised that the ECM acted as a barrier to successful T cell infiltration and tumor rejection. However, further experiments revealed that this was not the case but instead showed that an effective T cell response dramatically altered the density of ECM in the TME. Along with loss of ECM and high numbers of infiltrating T cells, responder tumors were distinguished by the development of lymphatic and blood vessel networks with specialized immune function. ECM-rich tumors exhibited a stem cell-like gene expression profile and superior tumor-initiating capacity, whereas such features were absent in responder tumors. Overall, these findings define an extended role for an effective immune response, not just in direct killing of tumor cells, but in widescale remodelling of the TME to favor loss of ECM, elimination of cancer stem cells, and propagation of adaptive immunity.