Cancer is not a single disease but rather a group of diseases characterized by the proliferation of cells that bypass regulatory checkpoints of the cell-cycle and/or escape induction of apoptosis (reviewed in Bocchetta and Carbone, 2004). In general, the proteins responsible for maintaining DNA and the cell cycle can be divided into six categories that include: (1) cytokines/growth factors (2) growth factor receptors; (3) intracellular signaling molecules; (4) transcription factors; (5) cell-cycle/apoptotic regulatory proteins; and (6) proteins that regulate DNA topology and metabolism (i.e., DNA topoisomerases).There is a high degree of cross-talk between proteins of the same class and between different classes of proteins, resulting in a network of highly synchronized events often referred to as a signal transduction cascade. Malignant cells usually acquire DNA mutations in one or more of these cell cycle or DNA regulatory proteins, which gives them growth or proliferative advantages over other cells. Since proteins function as part of a coordinated network with other proteins, even a single gene mutation can result in the propagation of additional gene mutations (i.e., if a gene mutation occurs in a DNA repair protein) or proliferative advantages (i.e., if a gene mutation occurs in a growth factor receptor). These genetic advantages disrupt the balance between cell proliferation and cell death. For example, the retinoblastoma protein (Rb) is encoded by the RB tumor suppressor gene and regulates the cell cycle by arresting DNA replication when DNA damage is present (Sellers, 1997). Mutations in the RB gene occur in 30 to 40% of all human cancers, thus permitting cells with DNA damage to divide endlessly (Merck, 2004).In addition to genetic mutations, tumor cells can also influence their microenvironment to favor their survival. For example, tumor cells secrete or promote the secretion of cytokines and growth factors to stimulate angiogenesis (Sivridis et al., 2003). The new blood vessels supply nutrients and additional cytokines that continue to activate cell signaling pathways that further tumor sustenance.In summary, cancer is a multifaceted disease that is propagated by multiple DNA mutations that are acquired via hereditary and natural means. The gene mutations can result in altered cellular homeostasis and confer growth and proliferative advantages. In turn, the collection of proteins that are involved in regulating the cell cycle and DNA replication/topology are the frequent targets of anti-cancer drugs. Thus, understanding the proteins involved in the intracellular cells signaling pathways, DNA replication/topology, and cell cycle regulation are the cornerstones of cancer research.References:Bochetta, M; Carbone, M. Oncogene. 2004, 23, 6484-6491.Merck Manual of Diagnosis and Therapy, 142 (11) Accessible [online] at http://www.merck.com.Sellers, W.R.; Kaelin, W.G. J. Clin. Oncol. 1997, 15, 3301-3312.Sivridis, E.; Giatromanolaki, A.: Koukourakis, M.I. J. Pathol. 2003, 201, 173-180.
