The mechanisms that endow cancer cells with the ability to proliferate can be grouped according to their role in the growth factor–induced signal transduction cascade and cell cycle regulation. Indeed, each one of the listed steps is susceptible to corruption in cancer cells.
http://ebooksmedicine.net
Cancers may secrete their own growth factors or induce stromal cells to produce growth factors in the tumor microenvironment. Most soluble growth factors are made by one cell type and act on a neighboring cell to stimulate proliferation (paracrine action). Normally, cells that produce the growth factor do not express the cognate receptor, preventing the formation of positive feedback loops within the same cell. This “rule” may be broken by cancer cells in several different ways.
Some cancer cells acquire growth self-sufficiency by acquiring the ability to synthesize the same growth factors to which they are responsive. For example, many glioblastomas secrete platelet-derived growth factor (PDGF) and express the PDGF receptor, and many sarcomas make both transforming growth factor-α (TGF-α) and its receptor. Similar autocrine loops are fairly common in many types of cancer.
Another mechanism by which cancer cells acquire growth self-sufficiency is by interaction with stroma. In some cases, tumor cells send signals to activate normal cells in the supporting stroma, which in turn produce growth factors that promote tumor growth.
The next group in the sequence of signal transduction is growth factor receptors. Some growth factor receptors have an intrinsic tyrosine kinase activity that is activated by growth factor binding, while others signal by stimulating the activity of downstream proteins. Many of the myriad growth factor receptors function as oncoproteins when they are mutated or if they overexpressed. The best-documented examples of overexpression involve the epidermal growth factor (EGF) receptor family. ERBB1, the EGF receptor, is overexpressed in 80% of squamous cell carcinomas of the lung, 50% or more of glioblastomas, and 80% to 100% of epithelial tumors of the head and neck. As mentioned earlier, the gene encoding a related receptor, HER2 (ERBB2), is amplified in approximately 20% of breast cancers and in a smaller fraction of adenocarcinomas of the lung, ovary, stomach, and salivary glands. These tumors are exquisitely sensitive to the mitogenic effects of small amounts of growth factors. The significance of HER2 in the pathogenesis of breast cancers is illustrated dramatically by the clinical benefit derived from blocking the extracellular domain of this receptor with anti-HER2 antibodies, an elegant example of “bench to bedside” medicine. In other instances, tyrosine kinase activity is stimulated by point mutations or small indels that lead to subtle but functionally important changes in protein structure, or gene rearrangements that create fusion genes encoding chimeric receptors. In each of these cases, the mutated receptors are constitutively active, delivering mitogenic signals to cells even in the absence of growth factors. These types of mutations are most common in leukemias, lymphomas, and certain forms of sarcoma.
Cancer cells often acquire growth autonomy as a result of mutations in genes that encode components of signaling pathways downstream of growth factor receptors. The signaling proteins that couple growth factor receptors to their nuclear targets are activated by ligand binding to growth factor receptors. The signals are trasnmitted to the nucleus through various signal transduction molecules. Two important oncoproteins in the category of signaling molecules are RAS and ABL. Each of these is discussed briefly next.