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《自然》雜誌:從原癌基因到致癌基因,從癌症機理到靶向抗癌藥(圖)

(2014-09-30 11:02:26) 下一個

Proto-oncogenes to Oncogenes to Cancer

By: Heidi Chial, Ph.D. (Write Science Right) © 2008 Nature Education 
Citation: Chial, H. (2008) Proto-oncogenes to oncogenes to cancer. Nature Education 1(1):33

文章來源:英國《自然》雜誌網站
(http://www.nature.com/scitable/topicpage/proto-oncogenes-to-oncogenes-to-cancer-883)
 
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What drives cancer cells to grow and divide uncontrollably turning into cancer? Studies of proto-oncogenes reveal some clues about how normal cellular processes mutate and go awry.

Figure 1 : Frequencies of oncogene mutations across human tumor types (各種癌症與原癌基因突變相關圖)
Frequencies (y axis) were calculated as percentages of tumor samples (x axis) from a given type that harbored an oncogene mutation (z axis) compared with the total number of samples of that tumor type.


One out of every two men and one out of every three women will develop cancer during their lifetime (American Cancer Society, 2008). The current list of known cancer genes includes 70 genes associated with germline mutations and 342 genes associated with somatic mutations. Generally speaking, however, mutations in two basic classes of genes—proto-oncogenes and tumor suppressor genes—are what lead to cancer. In fact, a recent high-throughput study of proto-oncogene mutations in 1,000 different tumor samples representing 17 different types of cancer showed that mutations in a set of 14 proto-oncogenes are associated with a high propensity for cancer. (See Figure 1 for a depiction of the association between these genes and certain forms of cancer.) Moreover, this study also revealed that the 14 proto-oncogenes in question are associated with diverse cellular functions (Thomas et al., 2007). But what drives cancerous cells to grow and divide uncontrollably and escape cell death, and just how are proto-oncogenes involved in this process?
 

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.

 

Table 2 : 致癌基因與癌症的例子  Examples of oncogene addiction: Studies in human cancer cell lines.
Treatment of these cell lines with an antisense oligonucleotide or an RNAi directed to the respective oncogene caused growth inhibition and in some cases decreased tumorigenicity and increased chemosensitivity.



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

By: Heidi Chial, Ph.D. (Write Science Right) © 2008 Nature Education 
Citation: Chial, H. (2008) Proto-oncogenes to oncogenes to cancer. Nature Education 1(1):33

http://www.nature.com/scitable/topicpage/proto-oncogenes-to-oncogenes-to-cancer-883
 
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