This gene signature represents a novel prognostic biomarker for patients with stage II colon cancer that can be applied to FFPE tumor samples.

Human tumors often contain slowly proliferating cancer cells that resist treatment, but we do not know precisely how these cells arise. We show that rapidly proliferating cancer cells can divide asymmetrically to produce slowly proliferating "G0-like" progeny that are enriched following chemotherapy in breast cancer patients. Asymmetric cancer cell division results from asymmetric suppression of AKT/PKB kinase signaling in one daughter cell during telophase of mitosis. Moreover, inhibition of AKT signaling with smallmolecule drugs can induce asymmetric cancer cell division and the production of slow proliferators. Cancer cells therefore appear to continuously flux between symmetric and asymmetric division depending on the precise state of their AKT signaling network. This model may have significant implications for understanding how tumors grow, evade treatment, and recur.quiescence | epigenetics | cell signaling | drug resistance T umors generally evolve through years of mutation and clonal selection (1). This favors the outgrowth of rapidly proliferating cancer cells over time. However, even advanced tumors contain many cancer cells that appear to be proliferating slowly (2). This proliferative heterogeneity correlates closely with time to clinical detection, growth, metastasis, and treatment response across all tumor types, but we still do not understand clearly how it arises. The rate of mammalian cell proliferation is generally determined by the time spent in G1 of the cell cycle. Critical genetic and epigenetic changes within cancer cells accelerate G1 transit, whereas a suboptimal microenvironment with imbalance of growth factors, nutrients, or oxygen can slow G1 progression (3). Therefore, individual cancer cells within a tumor are thought to vary significantly in their proliferative rate depending on the precise balance of these intrinsic and extrinsic factors. Interestingly, however, many tumor-derived cancer cell lines also produce slowly proliferating cells. These established lines have many acquired mutations that drive cell proliferation. They have also been grown ex vivo for years in a stable microenvironment to promote unbridled proliferation. These factors ought to favor a strong purifying selection against slow proliferators. We worked to understand how slowly proliferating cells seem to arise paradoxically in cancer cell lines.Results G0-Like Cancer Cells in Vitro. We began by studying MCF7, a highly proliferative, aneuploid, ER + /HER2 − human breast cancer cell line. This line displays significant proliferative heterogeneity despite mutations in CDKN2A and PIK3CA that cooperatively drive cell-cycle progression (4). We first hypothesized that slowly proliferating MCF7 cells might produce low levels of reactive oxygen species (ROS). This hypothesis was based on previous observations that slowly cycling hematopoietic, neural, and breast adult stem cells and cancer stem cells produce low levels of ROS (5-7). We stained MCF7 cells with 5-(and-6)chloromethyl 1-2′,7′-dichlorohydrofluorescein diacet...

Background:During metastasis, cancer cells migrate away from the primary tumour and invade the circulatory system and distal tissues. The stimulatory effect of growth factors has been implicated in the migration process. Placental growth factor (PlGF), expressed by 30–50% of primary breast cancers, stimulates measurable breast cancer cell motility in vitro within 3 h. This implies that PlGF activates intracellular signalling kinases and cytoskeletal remodelling necessary for cellular migration. The PlGF-mediated motility is prevented by an Flt-1-antagonising peptide, BP-1, and anti-PlGF antibody. The purpose of this study was to determine the intracellular effects of PlGF and the inhibiting peptide, BP-1.Methods:Anti-PlGF receptor (anti-Flt-1) antibody and inhibitors of intracellular kinases were used for analysis of PlGF-delivered intracellular signals that result in motility. The effects of PlGF and BP-1 on kinase activation, intermediate filament (IF) protein stability, and the actin cytoskeleton were determined by immunohistochemistry, cellular migration assays, and immunoblots.Results:Placental growth factor stimulated phosphorylation of extracellular-regulated kinase (ERK)1/2 (pERK) in breast cancer cell lines that also increased motility. In the presence of PlGF, BP-1 decreased cellular motility, reversed ERK1/2 phosphorylation, and decreased nuclear and peripheral pERK1/2. ERK1/2 kinases are associated with rearrangements of the actin and IF components of the cellular cytoskeleton. The PlGF caused rearrangements of the actin cytoskeleton, which were blocked by BP-1. The PlGF also stabilised cytokeratin 19 and vimentin expression in MDA-MB-231 human breast cancer cells in the absence of de novo transcription and translation.Conclusions:The PlGF activates ERK1/2 kinases, which are associated with cellular motility, in breast cancer cells. Several of these activating events are blocked by BP-1, which may explain its anti-tumour activity.

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