Signal Transduction in Cancer

Abstract

SUMMARYCancer is driven by genetic and epigenetic alterations that allow cells to overproliferate and escape mechanisms that normally control their survival and migration. Many of these alterations map to signaling pathways that control cell growth and division, cell death, cell fate, and cell motility, and can be placed in the context of distortions of wider signaling networks that fuel cancer progression, such as changes in the tumor microenvironment, angiogenesis, and inflammation. Mutations that convert cellular proto-oncogenes to oncogenes can cause hyperactivation of these signaling pathways, whereas inactivation of tumor suppressors eliminates critical negative regulators of signaling. An examination of the PI3K-Akt and Ras-ERK pathways illustrates how such alterations dysregulate signaling in cancer and produce many of the characteristic features of tumor cells.

Signaling Networks that Regulate Cell Migration

“…Oncogenic mutations leading to overproduction of PIP 3 are typically assumed to increase growth rates; but it is likely that many of the cancer-causing effects can also be attributed to alterations in the cytoskeleton (Kim et al 2011). Distortion of cell migration signaling networks plays a critical role in migration-related diseases such as invasive and metastatic cancer (Sever and Brugge 2014). The plethora of signaling pathways that converge on Rho GTPases means there is a very large potential set of loci for the misregulation of migration.…”

Akt signaling dynamics in individual cells

“…Sustained Akt activity under these conditions suggests that activation does not lead to significant negative feedback that otherwise would diminish responses over time. This presents an interesting contrast between the Akt and Erk signaling pathways, as both can be both stimulated by the same growth factors, but with the exception of carcinogenic mutations upstream of Erk, Akt remains persistently active whereas Erk becomes rapidly inhibited (De Luca et al, 2012;Sever and Brugge, 2015). It thus will be of interest to determine by live-cell imaging how Erk and Akt signaling behave in the same cells in response to growth factors, and whether and how their kinetics might vary.…”

Cell Death Signaling

“…This process is controlled in part by a p53-dependent apoptotic pathway, which is activated in response to aberrant mitogenic signals resulting from oncogene overexpression or mutation. As a consequence, evasion of apoptotic cell death is often a requisite to sustain oncogene transformation (see Sever and Brugge 2014).…”