Introduction to Proto-oncogenes
Proto-oncogenes are a group of genes that cause normal cells to become cancerous when they are mutated （原癌基因：突變後能使正常細胞癌變的基因） (Adamson, 1987; Weinstein & Joe, 2006). Mutations in proto-oncogenes are typically dominant in nature, and the mutated version of a proto-oncogene is called an oncogene. Often, proto-oncogenes encode proteins that function to stimulate cell division, inhibit cell differentiation, and halt cell death. All of these processes are important for normal human development and for the maintenance of tissues and organs. Oncogenes, however, typically exhibit increased production of these proteins, thus leading to increased cell division, decreased cell differentiation, and inhibition of cell death; taken together, these phenotypes define cancer cells. Thus, oncogenes are currently a major molecular target for anti-cancer drug design.
From Good to Bad: How Proto-Oncogenes Become Oncogenes
Today, more than 40 different human proto-oncogenes are known. But what types of mutations convert these proto-oncogenes into oncogenes? The answer is simple: Oncogenes arise as a result of mutations that increase the expression level or activity of a proto-oncogene. Underlying genetic mechanisms associated with oncogene activation include the following:
- Point mutations, deletions, or insertions that lead to a hyperactive gene product
- Point mutations, deletions, or insertions in the promoter region of a proto-oncogene that lead to increased transcription
- Gene amplification events leading to extra chromosomal copies of a proto-oncogene
- Chromosomal translocation events that relocate a proto-oncogene to a new chromosomal site that leads to higher expression
- Chromosomal translocations that lead to a fusion between a proto-oncogene and a second gene, which produces a fusion protein with oncogenic activity
Examples of Oncogenes
Figure 2： 細胞信息傳導阻斷導致癌症 Disruption of cell signaling can occur at several points and ultimately lead to cancer. Growth factor binding and the signaling pathway following receptor activation can be altered by growth factor gene amplification, such as increased EGF or TGF-alpha expression, or by receptor gene amplification or mutation, such as alterations in EGFR or ERBB2. In the cytoplasm, signaling molecules, such as RAS or RAF, may become locked in the active configuration. In the protein kinase cascade, disruptions may occur due to deletion or methylation-induced silencing of genes encoding negative regulators, such as PTEN and INK4A. Disruptions may also occur in transcription factor gene amplification or translocation, such as alterations in MYC and ERG-TMPRSS2. Within the nucleus, target gene inactivation, such as inactivation caused by mutations of the DNA repair gene BRCA1, and target-gene activation, such as activation of the cell cycle regulatory gene cyclin D, can disrupt intracellular signaling and lead to cancer.
Targeting Oncogene Addiction to Treat Cancer
各種癌症的靶向抗癌藥（２００８年）
Table1： In breast cancer, human epidermal growth factor receptor 2 (HER-2) can be targeted with trastuzumab in combination therapy. In chronic myeloid leukemia, BCR/ABL can be targeted with imatinib in monotherapy. In gastrointestinal stromal tumors, C-KIT can be targeted with imatinib monotherapy. In non-small-cell lung carcinoma (NSCLC), the epidermal growth factor receptor (EGFR) can be targeted with gefitinib or erlotinib monotherapy. In head and neck cancer and colorectal cancer, EGFR can be targeted with cetuximab in combination therapy. In pancreatic cancer, EGFR can be targeted with erlotinib in combination therapy. In breast, colorectal, and kidney cancer, vascular endothelial growth factor (VEGF) can be targeted with bevacizumab in combination therapy. In kidney cancer, the VEGF receptor or B-Raf can be targeted with sorafenib monotherapy.
Today, academic researchers, biotechnology companies, and pharmaceutical companies are continuing to develop approaches for targeting oncogene activity in the ongoing war on cancer (Chin & Gray, 2008). The approaches taken include using agents that bind and inhibit receptor activity, small RNA molecules that target oncogene expression, and drugs that inhibit the activity of downstream signaling proteins. The ability of cancer cells to evolve rapidly, combined with the heterogeneous nature of cancer cell populations, will continue to challenge researchers in years to come. Thus, like cancer cells, our approach to cancer therapy must also continue to evolve.
Reference and Recommended Reading
Proto-oncogenes to Oncogenes to Cancer
http://www.nature.com/scitable/topicpage/proto-oncogenes-to-oncogenes-to-cancer-883
