Paper #3

Kate Sakmann
4-7-08
Paper #3
Cancer and the Developing World: What HER1/EGFR
Can do to Help Lung Cancer Patients
In men worldwide, lung cancer is the most commonly diagnosed form of cancer; for women, it is the fifth most common. It has the highest mortality rate of all of the forms of cancer in both sexes. In addition, the second leading cause of death in the world is smoking, which is a cause of lung cancer. Although anti-smoking campaigns have caused the industrialized world to experience a decrease in the percentage of individuals diagnosed with lung cancer annually, the developing world has experienced the exact opposite. Their numbers of individuals diagnosed annually increased by nearly 20% between the years 1980 and 2002 [1]. There is no cure for cancer, but there are companies out there that are searching for prevention and treatment methods for those that have developed lung cancer, one of which is Tarceva.
The belief that cancer occurs most often in the industrialized world, since the individuals living there have longer life-spans on average than those living in the developing world, has become false. People in the industrialized world can develop cancer through smoking habits, exposure to carcinogens, and generally unhealthy lifestyles, all of which people in the developing world are becoming more exposed to since their average life span is increasing. In the 1950’s the life expectancy in the developing world was around 40. That number has increased dramatically, now amounting to roughly 65 [1]. According to journalist Michael Coren, “Developing countries’ share of new lung cancer cases jumped from 31 percent in 1980 to almost 49.9 percent in 2002” [1]. These individuals may also develop cancer through a few other harmful factors that the industrialized world is not necessarily exposed to. For example, cancer can result in people if they are exposed to carcinogens in smoked foods and preserved foods that are shipped to third world countries, or even from parasitic infections. Companies such as Tarceva are aiming to dramatically decrease the percentage of new patients that are diagnosed with cancer each year. This will be accomplished through studying the molecule HER1/EGFR, its normal function in relation to cells, the mutation that causes this normal function to go haywire, and methods to block this mutation.
Some of the processes and mechanisms of tumor development are still unknown, but the first step that is known is that a cancer cell begins developing when an oncogene is turned on. An oncogene codes for a cancer-causing DNA sequence. Because of this DNA sequence, cells are no longer programmed to experience apoptosis. The original gene, before the mutation, is called a proto-oncogene. Sometimes mutations and environmental factors are an added step to the turning on of the oncogene; also, a normal gene can have a mutation, thus becoming an oncogene. Examples of possible mutations include a change in protein activity and concentration, or the translocation (rearrangement) of chromosomes.
There are many methods of classifying oncogenes; receptor tyrosine kinase is one commonly used category of proto-oncogenes. Within the receptor tyrosine kinases is epidermal growth factor receptor (EGFR), located on the surface of a cells plasma membrane. Receptor proteins on the cell surface receive phosphate groups from receptor kinases. These receptor proteins transmit the signal to the target protein just below the surface of the cell. The amino acid tyrosine in the target protein then receives phosphate groups from tyrosine kinases. The kinases are what turn proteins on and off by adding phosphate groups. If the receptor is permanently turned on by one of the mutations listed above, the process will result in cancer. This process then can not be interrupted by extracellular signals.
Figure 1: The signaling pathway of EGFR and its accompanying map key [5].


The signaling pathway of EGFR is currently a highly researched area of study. The EGFR signaling pathway provided by Epitomics can be seen in Figure 1. A different research team, whose base is in Tokyo, Japan, is also designing a detailed map of the EGFR signaling pathway using CellDesigner software. A brief summary of the map, as told by Oda et al., states that:
The map includes EGFR endocytosis followed by its degradation or recycling, small guanosine triphosphatase (GTPase)-mediated signal transduction such as mitogen-activated protein kinase (MAPK) cascade, phosphatidylinositol polyphosphate (PIP) signaling, cell cycle, and G protein-coupled receptor (GPCR)-mediated EGFR transactivation via intracellular Ca2+ signaling. [2]

Tarceva and Herceptin are man-made molecules designed to permit the apoptosis, or programmed cell death, of cells and to prevent the proliferation of cancerous cells. These functions would allow each cell to return to normal cellular activity, rather than proliferating until a tumor is formed.
The goal of Tarceva is to block EGFR-mediated downstream signaling activity. Upstream and downstream are terms used to describe the specific order of molecular events. Upstream refers to the activation of cell membrane receptors and then the production of second messengers. The cell membrane receptors are activated upstream of the second messengers being produced. On the other hand, the second messengers can be produced downstream of the cell membrane receptors’ activation.

Figure 2: The four types of ErbB molecules, which is a receptor family that includes EGFR, are displayed in this figure. Each of these depictions represents one of the four receptor tyrosine kinase subfamilies of ErbB; the first image is EGFR (ErbB-1), the molecule of focus, and it is followed by HER2/c-neu (ErbB-2), Her 3 (ErbB-3) and Her 4 (ErbB-4) [3].

HER1/EGFR, depicted in the far left image of Figure 2, regulates cell division and cell death. If this protein malfunctions, cell division can go out of control, leading to the transition from normal cellular processes to tumirogenic processes. This EGFR-mediated cancer cell abundance can possibly be blocked if the EGFR tyrosine kinase domain is inhibited by Tarceva. The researchers of Tarceva believe that it would prevent the EGFR from mediating signaling activity downstream. It would inhibit this signaling by attaching to the active site of the tyrosine kinase, which is on the inside of the plasma membrane, so that ATP could not bond to the active site and cause the EGFR to catalyze proliferation [4]. Thus, Tarceva would fight cancer through competition and would be greatly helpful in the treatment of lung cancer, in addition to the treatment of pancreatic cancer.
In addition to lung cancer, breast cancer is another widely problematic form of cancer. According to a recent study, a higher percentage of women die of cancer in the developing world than in the industrialized world, which threatens not only one life, but two if the woman is carrying an unborn child. Trastuzumab (Herceptin) is a treatment option for individuals who develop breast cancer. Herceptin specifically targets the HER2 protein and HER2/neu gene which is produced in excess in women with breast cancer. This treatment is very effective in women that are in stages II, III, or IV of breast cancer [7]. Herceptin acts similarly to Tarceva, but on the HER2 protein rather than HER1. HER2 is depicted in the second image (to the right of HER1) of Figure 2.
Since life expectancies are increasing in the developing world, the individuals there are being exposed to more of the same carcinogens that people in the industrialized world have been exposed to for nearly a century. Therefore, cancer is not only a continuing problem for industrialized countries, but also an increasing problem in developing countries. If companies that produce possible treatments, such as Tarceva and Herceptin, can manufacture effective preventive medicines or even cures for cancer, then a large portion of the world’s population will be rid of a widely problematic disease.

Works Cited
[1] Coren, Michael. "Study: Cancer No Longer Rare in Poorer Countries." CNN.Com. 10 Mar. 2005. 04 Apr. 2008 .
[2] Oda, Kanae, Yukiko Matsuoka, Akira Funahashi, and Hiroaki Kitano. "A Comprehensive Pathway Map of Epidermal Growth Factor Receptor Signaling." Molecular Systems Biology (2005). 4 Apr. 2008 .
[3] "ErbB." Wikipedia. 18 Nov. 2007. 4 Apr. 2008 .
[4] "Tarceva Mechanism of Action." YouTube. 1 July 2007. 4 Apr. 2008 .
[5] "EGFR Pathway." Epitomics. 2007. 14 Apr. 2008 .
[6] Kalata, Katy. "Gold Nanoparticles and Cancer Cell Detection." YouTube. 27 May 2007. 14 Apr. 2008 .
[7] "Herceptin." Breastcancer.Org. 7 Apr. 2008. 14 Apr. 2008 .