Deregulation of cell signaling in cancer

Abstract

Oncogenic mutations disrupt the regulatory circuits that govern cell function, enabling tumor cells to undergo de-regulated mitogenesis, to resist to pro-apoptotic insults, and to invade through tissue boundaries. Cancer cell biology has played a crucial role in elucidating the signaling mechanisms by which oncogenic mutations sustain these malignant behaviors and thereby in identifying rational targets for cancer drugs. The efficacy of such targeted therapies illustrate the power of a reductionist approach to the study of cancer.

Keywords: Cancer cell biology; Cell signaling; Targeted therapies; Tumorigenesis.

Figure 1

Hallmarks and oncogenic functions. Deregulated signaling endows tumor cells with several attributes (hallmarks or traits), which in turn sustain oncogenic functions. Increased cell proliferation, decreased cell attrition, and invasion are necessary for oncogenesis and are thus categorized as driver functions; genetic instability and a permissive tumor microenvironment are provisionally classified as fostering functions.

Figure 2

Receptor tyrosine kinase signaling. (a) The membrane-proximal events and major effector pathways activated by RTKs are depicted. Ras and AKT activate multiple targets. Signaling strength and duration are controlled by negative as well as positive feed-back loops. (b) Major signaling pathways activated by Ras proteins and multiple mechanisms of negative feed-back regulation. (c) Major target-effectors and pathways regulated by AKT.

Figure 3

Adhesion receptor signaling. The major signaling mechanisms underlying the ability of integrins to buttress mitogenic signaling and that of cadherin to exert the opposite effect are depicted.

Figure 4

TOR signaling. Multiple inputs regulate the AKT-mTORC1 signaling axis. mTORC1 in turn regulates anabolic processes by phosphorylating multiple target-effectors. The inset illustrates two major mechanisms of negative feedback regulation.

Figure 5

Metabolic reprogramming in cancer. The major mechanisms by which oncogenic alterations alter flux through multiple metabolic pathways are illustrated.

Figure 6

Intrinsic tumor suppression. Mutant Ras and overproduced Myc induce senescence or apoptosis through common as well as distinct mechanisms.