Ohio State University
Publication Date: January 1, 2015
Cancer is one of the biggest killers among all diseases to affect humans (Society, 2010). 1.6 million people in the United States are expected to develop cancer this year alone (Howlader N, 2011b). It was estimated by the National Cancer Institute that 36,540 people would be diagnosed in 2010 with oral cancer in the US and 7,880 of them would die of it. In 2008, the total deaths from cancer were estimated to be about 7.6 million or 23.1% of all deaths, giving it second place below heart diseases by only 2.9%. More than 70% of all of these cancer-related fatalities occurred in low and middle-income countries. Cancer continues to be a significant health concern due to its high mortality rate and unpredictable response to treatment. It occurs most often in black men and white women, though death rates have been reported to be higher among black women (Howlader N, 2011a). This is possibly due to poverty, lack of health insurance, and limited access to health care delay in diagnosis (Howlader N, 2011a). Cancer can affect all types of tissue in the body, from the brain to blood cells (Society, 2010).
In the body, cells multiply and divide constantly, a process that is necessary to repair damage, replace old cells, and for the body to grow. When cells approach each other, they stop dividing by a process known as contact inhibition (Eagle & Levine, 1967). Additionally, they have mechanisms to stop mutated cells from creating more mutated cells such as tumor suppressor pathways that help fix the DNA and other processes that halt the division of the cells and cause it to die. Sometimes the cells’ DNA is mutated or changed and they lose this inhibition, multiplying and piling up on each other and creating a tumor. The new cells kill the normal, healthy ones and may metastasize into vital organs, leading the body to begin fighting and killing itself (National Cancer Institute, 2011).
Several lines of therapy have emerged to treat cancer- from surgical removal to radiation and chemotherapy to kill cancer cells, to viral vectors that carry genes capable of modifying a cell’s DNA to therapies that can choke off the blood supply to the cancer cells. All of these therapies have evolved as our understanding of the disease process and its pathogenesis has expanded.
The purpose of this article, therefore, is to review the literature with respect to historical development of the etiology of cancer and how this has affected therapy, with a special focus on research advances in angiogenesis and its effect on therapeutic intervention.
Cancer and its Causes: A Historical Perspective
Cancer, or as it’s medically known, malignant neoplasm, was a term first derived from the Greek word, “carcinos”, which referred to a crab (WHO). This was due to the fact that the veins of the tumor stretched like spindly wires on all sides similar to the legs of a crustacean. Hippocrates, who drew and recorded observations of outwardly visible tumors (since Grecian laws prevented him from opening the cadaver), made these observations, leading to the naming of this disease (Sudhakar 2010).
The early Egyptians believed that cancer took two forms: benign and malignant. The Ebers and Smith papyruses detail the surgical and pharmacological treatments advocated for these two forms. The ancient Egyptians believed that both forms were a curse from the Gods- the benign tumor was a punishment from lesser evils while the malignant forms expressed the Gods wrath for serious human crimes. All treatment involved propitiating the deities with sacrifices and gifts.
From the times of Hippocrates and Galen, there has been a concerted search for the causes of cancer. These early researchers believed that health was dependent upon a balance between the four humors (or fluids) in the body: blood, phlegm, black bile and yellow bile. When these fluids were not in equilibrium, diseases occur. An excess of black bile was attributed to the etiology of cancer (Achen, 1998).
The Humoral Theory, described above, was in vogue until the Middle Ages, when it was replaced by the Lymph Theory. According to this theory, health depended upon continuous and regular fluid movement through the body. Degenerating lymph that was excreted from blood, was held to be the cause of cancer.
However, concepts changed in the mid-nineteenth century, when it was discovered that cancer was made up of cells, and was not simply a fluid filled sac. Muller and his student developed the Blastema Theory, which hypothesized that cancer cells developed from cells that are derived from normal tissues (Blast). The discovery that cancers were solid tumors and not fluid filled sacs quickly advanced research on their etiology. Chronic irritation and trauma were held to be critical in the development and progression of the disease.
These facts are critical to the development of oncology as a science. As we will see in the following sections, the Lymph theory and Blastema theory, so summarily dismissed in the early 19th century, have significant merit. Their resurgence and acceptance led to the development of targeted chemotherapy, radiation therapy and anti-angiogenic therapy.
Causes of Cancer- Developments In The 20th Century
The development of the microscope in the 19th century gave birth to the field of scientific oncology. Not only could cellular and ultrastructural changes be studied and used to diagnose cancers originating in different tissues, but also the accuracy of surgical resection be confirmed. Surgery became a viable treatment option and the edges of the surgically resected tissue had to lie in normal tissue for the cancer to be completely removed. The microscope allowed the surgeon to confirm that the tumorous growth had been completely removed.
The development of cell culture and the recognition of carcinogens gave rise to an important paradigm- the concept of susceptibility. The origin of cancer was recognized as a mutated gene, which occurs when cells are repeatedly exposed to cancer-causing substances like cigarette smoke, inflammation, alcohol or sunlight. The scientific term for these cancer-causing substances is ‘carcinogens’, due to the fact that they cause our genes to change and increase the likelihood for cancer (cancerresearchuk.org). Repeated exposure to carcinogens disrupts normal cell cycle and cell division. Normal cells stop dividing once they come into contact with a neighbor – a phenomenon known as contact inhibition. This is the reason why we have smooth skin and mucous membranes lining our body. Mutations in the gene can disrupt contact inhibition, causing cells to continue dividing even when they come into contact with their neighbor. This leads to cells growing on top of each other, and forming a mass or tumor. Genetic mutations can affect the individual or be passed on to the offspring. These genetic mutations, when passed on to the offspring, can increase susceptibility to disease however most mutations will not lead to cancer unless the individual is exposed to the carcinogen. For example, it is known that mutations in the BRCA1 and BRCA2 genes increase the risk for breast cancer by 80%. The Hollywood actress Angelina Jolie elected to undergo a double mastectomy (removal of both her breasts) because she discovered that she carries the BRCA1 gene and her mother died of breast cancer at a very young age. However, not every woman with a BRCA1 mutation will develop breast cancer. Exposure to environmental insults (inflammation caused by fatty breast tissue, alcohol, smoking, infertility) is critically important in development of disease in these susceptible women.
The twentieth century also saw recognition of several risk factors for cancer such as diet, alcohol use, hormone levels, or exposure to carcinogens, but smoking quickly outweighed these by far (Kingsley, et al., 2011). Cigarette use began to be linked to types of cancer like lung, mouth, bladder, colon, and kidney cancers, and is responsible for one-third of all cancer-related deaths in most countries (Natarajan & Eisenberg, 2011). In 2010, the Centers for Disease Control (CDC) estimated that nearly 20% (45.3 million) of U.S. adults were current cigarette smokers, and that almost every other smoker will be killed by cancer (http://www.cdc.gov/tobacco/data_statistics/tables/index.htm). Research showed that smoking caused cancer by several mechanisms, by increasing inflammation, as well as by causing changes in the cell’s DNA- a process known as epigenetic modification.
A cell carries out its functions when molecules known as ribonucleic acids or RNA read the genetic code in the DNA and make proteins based on this information. The RNA can read the DNA if it is uncoiled and presented as a long strand. Sometimes, mutagens such as cigarettes smoke cause the DNA to coil tightly (epigenetic modification) and prevent the RNA from reading the genetic information correctly (a phenomenon called DNA silencing), leading to malformed proteins that do not carry out cellular functions in a normal manner, thus forming to abnormal cells. This is the starting point of cancer. If this epigenetic modification is inherited by the offspring, it leads to genetic mutations in the child, increasing disease susceptibility.
Another important development was identifying inflammation as a leading cause of cancer. Inflammation is the normal response of tissues to infection or injury and can be seen in the body as redness, swelling, pain, increased heat in the area, and possible loss of function (Jeng et al., 2003; Schottenfeld & Beebe-Dimmer, 2006). At the molecular level, inflammation occurs through release of molecules called cytokines (Stathopoulou, Benakanakere, Galicia, & Kinane, 2010). These molecules are important for the growth of immune cells like neutrophils and lymphocytes, which secrete acids, hydrogen peroxide, or antibodies that kill the infection or wall off the area of injury. Of the sources of cancer, inflammation due to microbes is among the three most common, causing almost fifteen percent of cancers worldwide (Rakoff-Nahoum, 2006). Sometimes when certain bacteria infiltrate the cell, they mutate the DNA to create cancer cells (Ostrand-Rosenberg & Sinha, 2009). The body also releases certain chemicals to fight infections; the byproducts of these chemicals are oxygen and nitrogen ions, which are possible mutagens. Inflammation also aids the cell in losing its mechanisms that inhibit its multiplication once it has mutated, for the body sends out signals to fix what caused the inflammation, calling for the cells to continue multiplying and allowing for the tumor to grow (Rakoff-Nahoum, 2006). Smoking increases inflammation in different cells types in the human body, creating mutations that may lead to cancer by altering the response of normal cells to bacteria (Lee, Taneja, & Vassallo, 2012).
Thus, the twentieth century firmly established the fact that the basis of cancer is genetic, either inherited susceptibility or epigenetic modifications. Several factors contribute to this process, from chronic inflammation to smoking to alcohol to sunlight and bacteria. These same factors could also act as triggers for cancer induction in susceptible individuals. Recognizing the critical role that inflammation plays in the pathogenesis of disease has led to several important preventive measures in cancer prevention. For example, the role of inflammation in the etiology of colon cancer has led to preventive antacid and probiotic therapy for risk reduction in susceptible individuals (Achen, 2006). Also, the knowledge that obesity leads to release of profuse amounts of pro-inflammatory agents has focused preventive care on reducing fatty tissues in the breast as well as general weight and waist circumference reduction (Achen, 2006).
Breakthroughs in the Twenty-First Century
A major breakthrough in understanding cancer came with the idea of “Angiogenesis”, or the creation of new blood vessels (cancer.org).
Angiogenesis is a process involved in the formation of new blood vessels, which occurs naturally in the body during wound healing, embryonic development, reproduction and also plays a vital role in tumor growth.
The first scientific records of angiogenesis were recorded by John Hunter, who suggested that, “proportionality between vascularity and metabolic requirements occurs in both health and disease (Adair, 2010).” Blood vessels, the organ system in which the process of angiogenesis occurs, are the first to develop in an embryo. The circulatory system, with its complex network of arteries, veins and capillaries develops along with the growing individual and reaches a stable state in adulthood (Nishida, 2009).
When an injury occurs, several events occur in concert. The site of injury becomes a region of low oxygen tension, or ischemia. The surrounding cells secrete growth factors, for example Angiogenin, Eotaxin, Platelet Derived Growth Factor and Vascular Endothelial Growth Factor, among others. These growth factors lead to the development of new blood vessels that in turn bring in nutrients and cells to repair the damage caused by injury. A similar event occurs in an area of infection, except that in this case, the new blood vessels bring in immune cells to destroy or control the infection.
Angiogenesis in tumors is the formation of new blood vessels through which the nutrients and oxygen is been supplied, which assist tumor growth. Angiogenesis not only aids in tumor growth but also helps in metastasis that is travelling of the tumor along the blood stream (Natarajan, 2011). In 1971, Dr. Judah Folkman noticed that tumor growth was angiogenesis-dependent, and that solid tumors became much more aggressive and metastatic following an increased blood supply (Folkman, 1971). His findings were very exciting within the field of cancer therapy because over 90% of all cancers present as solid tumors (Abdelrahim, 2010). Folkman was one of the main pioneers involved with angiogenesis targeting anti-cancer therapy, and along with his most recognized discovery in 1971; he also discovered the first anti-angiogenic compound in cartilage (Brem & Folkman, 1975).
Cancer cells are especially dangerous due to their ability to spread to adjacent organs. Tumor cells often penetrate blood vessels in order to be carried to another site where they can once again form another aggressive tumor, a process known as metastasis (Nishida, 2006).
The growth of a tumor and the rate at which it grows varies in each person due to their bodies’ individual rates of angiogenesis (Nishida, 2006). Cancer is common in people above the age of 50, the reason behind which has to do with angiogenesis.
Tumor associated vasculature are irregular and unstable due to the increase in proangiogenic proteins such as Vascular Endothelial Growth Factors (VEGF) (Yano, 2006). Along with the creation of new blood vessels, more blood can be pumped through the entire body, fueling the growth of a cancer tumor.
Several treatments for cancer are now targeted towards using drugs or other substances that prevent the natural process of angiogenesis. Although Judah Folkman first proposed this in the 1970s, the idea itself was not carried out until 2004 (cancer.org).
Anti-angiogenic therapy is solely based on the activation or inhibition of the enzymes that cause angiogenesis. Because cancer cells require blood flow for growth and metastasis, anti-angiogenic therapy proves effective by targeting the blood vessels and slowing down or stopping the process of creating new blood vessels. “Five classes of angiogenic antagonists are currently in clinical trials: inhibitors of proteases (inhibit the synthesis of MMP); endothelial cell migration and proliferation; angiogenic growth factors; matrix proteins on the endothelial cell surface such as integrins, copper; and inhibitors with unique mechanisms (Nishida, 2006).”
A prominent angiogenic inhibitor is Angiostatin, which is known for inducing apoptosis in endothelial and tumor cells (Nishida, 2006). By doing this, they don’t directly attack the cancer cells, but rather the blood vessels connecting to them. Due to their high rates of growth and inability to undergo apoptosis, tumors require their own independent vascular system. Therefore, by initiating anti-angiogenesis, these substances can decrease the growth of a large cancer tumor (cancer.org).
Overall, cancer has been proven to be the cause of more deaths than any other disease simply due to the fact that no cure has been found. Anti-angiogenic therapy and chemotherapy are not considered cures, but rather treatments because they do not completely kill the cancer tumor. Anti-angiogenic therapy especially is so effective because it prevents metastasis and growth of each individual cancer cell. To achieve maximum benefit, though, anti-angiogenic therapy should be combined with chemotherapy and radiation therapy (Nishida, 2006).
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Picture taken from http://www.telegraph.co.uk