Oncogene-induced plasticity and cancer stem cells.

The cancer stem cell hypothesis is an evolving concept of oncogenesis that has recently gained wide acceptance. In its simplest form this hypothesis suggests that many if not all tumors arise by consecutive genetic changes in a small subpopulation of cells termed cancer stem cells. These cells have the capacity to sustain tumor growth and are defined by three features: self-renewal, differentiation into the cell types of the original cancer and potent tumor formation. The definition of a cancer stem cell does not necessarily imply its origin from a stem, progenitor or differentiated cell. Hence, the term tumor or cancer initiating cell is often used instead to avoid any implications. Here, we propose a model suggesting that tumor cells progressively acquire stem cell properties as a consequence of oncogene-induced plasticity. The basis of our proposal are data from several experimental in vitro and in vivo models demonstrating reprogramming events triggered by specific combinations of oncogenes. These oncogene combinations not only induce cell lineage switches but also drive the reversal of ontogeny within cell lineages during tumor progression to metastasis. In this perspective article we will summarize the experimental evidence that illustrates our concept and discuss its implications for tumor formation and tumor therapy.

Ras oncogenes and their downstream targets.

RAS proteins are small GTPases, which serve as master regulators of a myriad of signaling cascades involved in highly diverse cellular processes. RAS oncogenes have been originally discovered as retroviral oncogenes, and ever since constitutively activating RAS mutations have been identified in human tumors, they are in the focus of intense research. In this review, we summarize the biochemical properties of RAS proteins, trace down the evolution of RAS signaling and present an overview of the spatio-temporal activation of major RAS isoforms. We further discuss RAS effector pathways, their role in normal and transformed cell physiology and summarize ongoing attempts to interfere with aberrant RAS signaling. Finally, we comment on the role of micro RNAs in modulating RAS expression, contribution of RAS to stem cell function and on high-throughput analyses of RAS signaling networks.

Raf kinases: oncogenesis and drug discovery.

Raf kinase signaling has been thoroughly investigated over the last 20 years. A-Raf, B-Raf and C-Raf, the 3 mammalian members of the Raf family, are involved in a variety of cellular processes such as growth, proliferation, survival, differentiation and transformation. The detection of B-RAF mutations in a wide variety of human cancers, the description of wildtype and mutant B-RAF as tumor antigens in melanoma and the promising outcome of clinical trials evaluating the Raf inhibitor Nexavar (Sorafenib, BAY 43-9006) have sparked a broad interest in the scientific community. After a short historical detour and an introduction into Raf kinase signaling, we are going to discuss here recent outcomes of Raf kinase research with respect to tumor formation and give an overview on current efforts to develop anticancer therapies interfering with aberrant Raf kinase signaling.