The Role of Signaling Pathways in Tumor Growth, Survival, and Angiogenesis

Volume 1, Number 1
Release date: January, 2007 - Expiration date: January 2008
Estimated time to complete activity: 1.5 hours
Educational credits: 1.4 contact hours

Click here for a Printer friendly file.

Pamela Hallquist Viale, RN, MS, CS, ANP, AOCNP
Until recently, chemotherapy, radiation, and surgery have been the mainstays of treatment for most types of cancer. While these approaches have saved countless lives and are still used extensively, they are not without significant toxicities. Side effects from chemotherapy and radiation arise from the fact that neither modality is particularly selective, exposing tumor cells and healthy host cells alike to the toxic effects of therapy. Chemotherapy in particular targets rapidly dividing cells, an approach that attacks tumor cells and certain types of host cells, including white and red blood cells, epithelial cells lining the gastrointestinal tract, and hair follicles. The destruction of these cells causes numerous unwanted effects including myelosuppression, diarrhea, mucositis, and hair loss. Furthermore, some chemotherapy agents preferentially attack certain organ tissues, as is the case with the cardiotoxicity caused by anthracyclines (Lefrak, Pitha, Rosenheim, & Gottlieb, 1973), which can lead to congestive heart failure. While chemotherapy remains an important element of cancer treatment, current research goals aim to provide safer therapies with fewer side effects.

An entirely new therapeutic class of drugs called targeted agents has emerged over the past decade. Although their mechanisms of action can be quite diverse, all drugs in this class specifically target one or a limited number of cellular components, thereby selectively attacking those cells containing the target (i.e., tumor cells) while sparing all others. Because of this selectivity, targeted agents tend to have fewer associated toxicities than traditional chemotherapy, although they do have their own unique set of side effects, which may include dermatological, cardiovascular, and gastrointestinal disturbances. Ideally, a targeted agent will possess several characteristics. Most important is its ability to target a component that is present on the tumor cells, but absent on nontumor host cells. It is also desirable for the drug to target an essential component of a key tumor process, such as survival, proliferation, metastasis, or angiogenesis.

SIGNAL TRANSDUCTION VIA SIGNALING PATHWAYS
Advances in our understanding of the development and progression of cancer have led to the discovery that oncogenes can alter the function of numerous cellular processes through the overexpression or mutation of key signaling components. These alterations contribute to the tumor cell’s ability to proliferate, inhibit apoptosis, and migrate. As already discussed, a desirable targeted agent will attack that which is both preferentially expressed on tumor cells and essential to a process related to the tumor’s malignant phenotype. Therefore, those signaling components that are overexpressed or mutated within a tumor cell are often excellent therapeutic targets.

Signaling processes, such as proliferation or survival, occur via signal transduction pathways that are typically composed of a ligand, a transmembrane receptor, and numerous cytoplasmic signaling intermediates (Figure 1).

Signal transduction is the transmission of an extracellular signal into the cell, where it produces a functional change. This transmission is often called a signaling cascade, as the signal is passed in succession from one intermediate to another. Signaling is initiated by a soluble ligand, such as a growth factor, hormone, antibody, or external drug, which through its binding causes the dimerization of cell surface receptors. The most common type of receptor involved in the cellular processes is the receptor tyrosine kinase (RTK), a receptor with an extracellular domain to which a ligand binds and an intracellular tyrosine kinase domain that has enzymatic activity (Figure 2). Dimerization, which can occur either through the pairing of two identical monomers (homodimerization) or two heterogeneous monomers (heterodimerization; Figure 3), activates the receptor, leading to the phosphorylation and activation of downstream signaling intermediates. In this way, a signal is transmitted through the pathway, eventually resulting in the regulation of a particular cellular process.

CRITICAL CANCER CELL SIGNAL TRANSDUCTION PATHWAYS
Signal transduction as described above is not a function exclusive to tumor cells. It is a necessary function of every cell, and thousands of distinct intracellular signals within a cell are transmitted in this manner. It is the dysregulation of certain signal transduction pathways by oncogenes that leads to carcinogenesis and tumor progression. The following section reviews several of these pathways and their corresponding therapeutic targets.

Page 1