We’re drowning in
information and starving for knowledge
Rutherford D. Rogers
| Readings | Resources | Outline | Objectives | Questions | Multiple Choice | Lexicon | Updated 04/12/00 |
Who am I? I was born in New York in 1939. Dr. J.M. Bishop and I demonstrated that cancer can be trigger by normal cellular genes, called oncogenes, that have malfunctioned. We shared the Nobel Prize for Medicine in 1989
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| Alpha feto protein and CEA in cancer |
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| T Cell Receptor |  |
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URL --> http://www.cancerresearch.org/immresp.html
URL --> http://www.mdacc.tmc.edu/~bioimt/
DEFINE THE FOLLOWING KEY TERMS:
| Antibody dependent cell mediated cytotoxicity (ADCC) | benign tumour | carcinogens |
| tumour specific transplantation antigens | natural killer cells (NK) | immunotoxins |
| immalignancymune surveillance | Specific immunotherapy | neoplasm |
| non specific immunotherapy | tumour specific antigens | oncogens |
| Lymphokine activated killer cell(LAK) | malignant tumour | tumour |
| tmour associated transplantation antigens | oncofetal antigens | cancer |
| tumour associated antigens | proto oncogens | metastasis |
ON COMPLETION OF THIS SECTION THE STUDENT SHOULD BE ABLE TO:
CANCER LECTURE: Dr. Dufresne
Each of you reflects a miracle of complex cellular organization. You are made up of trillions of cells reflecting about 100 different cell types. The majority of the cell types are involved in keeping you alive; these cells are termed somatic cells and include the cells that make up your liver, skin, blood, kidney, brain and so forth. A small proportion of your cells are involved in passing on your genetic information to your progeny; these cells are termed sex cells and include the gamete producing cells and the gametes (i.e., egg and sperm) they produce. All of your cells are organized in highly complex structural and functional tissues, organs and organ systems that allow you to live and to reproduce, in other words to survive. What’s even more amazing is that this complexity started from the division of one single cell -the fertilized egg. This cell divided to produce two descendants identical to the original cell. In this process, the DNA was duplicated to produce two complete copies of the genetic information; one copy was distributed to each end of the cell; and finally the cell split in two. This process of cell division was repeated over and over again during early development within the womb. Early in this process, cells responded to environmental signals and became destined to particular functional fates -for example, sex cells, muscle cells, liver cells, nerve cells and so forth. Their descendants inherited the same destiny potential. Thus the number of each cell type increased and allowed the formation of specific tissues and organs.
During the nine-month period in the womb, cell division led you from a single cell to a multi-trillion celled, functional child. But the wonder of cell division doesn’t stop here. After birth you grew. For this to occur, cell division in the young exceeds cell death, so the child increases in size. When you stop growing, the processes of cell division and cell death are balanced to produce a steady state. This steady state varies with the type of cell. Adult intestinal cells, for example, divide rapidly -every day or so. Liver cells on the other hand divide very slowly -every couple of years. If however, your liver is damaged, liver cells around the area of damage are activated to divide more rapidly (e.g., every day or so) until the damage is repaired. Then they go back to dividing slowly. Yet other cells, such as mature nerve and brain cells never divide; nor do they respond to damage "wake-up" calls. At present you cannot reverse damage to these cells -there is no replacement and there is no repair. As we age, cell death begins to exceed cell division. This leads to the "shrinkage" phenomenon most of us will experience as we age, and ultimately to death.
I began to-day’s lecture with this cell division story for a couple of reasons. The first is to point out that cell growth and division are carefully regulated processes. In fact scientists have now determined that the root of this regulation is in the genetic material -specifically in genes that control cell growth, division, function and death. The second reason is to point out that errors in the regulation of cell growth and division can have devastating effects on the individual and beyond.
CANCER
Very occasionally, alterations in the genes that control cell growth and division occur. The cell that sustains these mutations then begins to grow and divide even when the body has no need for it. Since the descendants of this mutated cell inherit these same abilities, this leads to a mass of cells, or tumour, that can expand indefinitely. Moreover, this expansion is not restricted to the local environment. Some cells within this tumour can invade surrounding tissues and even spread to other sites of the body. Tumour cells with these properties are defined as malignant and the tumours themselves are termed CANCER. A disease everyone in this room will be affected by -directly or indirectly. According to current statistics for North America, one out of every three people will develop cancer; one out of every four will die from it. These statistics are startling and their implications devastating. What can be done? The first step is to understand the history of these disturbing statistics.
HISTORY
Even before the father of medicine, Hippocrates, gave cancer its name 2,500 years ago (from Greek term karkinos meaning crab), it has been identified as a scourge. Despite its identification, it was a rare disease until the 20th century. In 1850, for example, cancer accounted for about 1 in 190 deaths in North America. Now the incidence of cancer is 1 in 3, while the mortality from cancer is approximately 1 in 4. Ironically, these increases have occurred despite tremendous advances in medical research and, in fact, parallel social and economic improvements that decreased the number of deaths associated with infectious disease (e.g., influenza, pneumonia, and tuberculosis). This decrease was largely due to preventative measures including: a) filtration and chlorination of water, b) removal and treatment of sewage, c) pasteurization of commercial dairy products, d) adaptation of antiseptic practices, e) preservation and storage of food, and f) development of specific vaccines and antitoxins. The introduction of antibiotic use also played an important role in decreasing the frequency and severity of infectious diseases. [NOTE: Our overindulgence in the use of antibiotics has introduced a new problem –resistant bacterial strains. This, in turn, is resulting in the reintroduction of infectious diseases (e.g., tuberculosis) once thought "extinct".]
The decrease in deaths from infectious diseases over the course of the 1900s has had significant effects on the population structure and the age distribution. First, there has been increased survival in members of the population targeted by infectious diseases, namely the very young and old of both genders and females in adolescent and reproduction years. Second, there has been a dramatic increase in the life span of both genders from 50 at the turn of the century to approximately 78-84 years in 1995). This latter effect is particularly relevant to the parallel increase in cancer since we now know that the incidence and mortality rates for cancer increase exponentially after the age of 50. At the simplest level, this increase after age 50 reflects the time it takes for a normal cell within your body to be converted to a cancer cell, and the time required for that cancer cell to divide and form a cancer tumour. [NOTE: It should be obvious that this does not imply that cancer does not develop in persons under 50. Childhood cancers are second only to accidents as the cause of death in children.] How then does a normal cell within your body become converted to a cancer?
Research has established that cancer represents a fundamental breakdown in cellular behavior that begins with alterations in genes (i.e., DNA) that control cell growth and division. Once a normal cell has been transformed to a cancer cell, many additional, significant changes have to occur before this cell forms a tumor we identify as a cancer. For example, it continues to divide even when its normal counterparts do not, then cells from the growing mass invade surrounding tissue (i.e., invasion) and after breaking away from the primary tumour, spread to other sites of the body by means of the blood and lymph systems (i.e., metastasis). Most of these cells are destroyed by the immune system; however, it is clear that others do not. [NOTE: One of the reasons for this escape seems to be that cancer cells are usually closer in their properties to cells found in the developing fetus. Fetal cells are able to invade and to spread; however, these processes are controlled and eventually are suppressed. The similarity of many cancer cells to fetal cells also explains the difficulty in targeting cancer cells during treatment.]
Spontaneous versus Environmentally-induced Cancers
Alterations in DNA (i.e., mutations) can occur spontaneously in any of the 100 different types of cells as a result of errors in DNA replication or in the processes involved in cell division (e.g., mitosis). Most of these mutations occur in the body cells of an individual (i.e., somatic cells); however some can occur in the cells that produce sperm or egg, or in the sperm or egg themselves (i.e., sex cells). [IMPORTANT NOTE: As mentioned in the first paragraph of this lecture, the majority of the trillions of cells in your body are somatic cells (e.g., liver cells, muscle cells, skin cells and so forth). Mutations in somatic cells affect the individual (i.e., liver cancer or skin cancer) but not his/her children. In contrast, mutations in the individual’s sex cells can affect the individual’s children, but rarely affect the individual. Mutations of this latter type are associated with cancers that run in families (i.e., familial cancers). If there is time at the end of this lecture series, the concept of familial cancers will be discussed.] While spontaneous mutations are extremely rare, the billions of divisions your cells undergo each day can theoretically result in 1000-2000 mutational events that could lead to cancer. But do the high cancer numbers reflect this spontaneous mutation potential? The answer to this question is no. In fact we know that 90% of all cancer mutations are induced by cancer-causing agents in the environment. How do we know this?
The first association between the environment and cancer was made in 1775 by Sir Percival Pott, a London physician whose patients included young chimney sweeps. Pott observed that these young males had a higher incidence of cancer of the scrotum than young males in other professions. He hypothesized that the soot that had accumulated within the folds of the scrotum had induced the cancer he observed. This hypothesis remained untested until the 20th century when it was supported. In fact, the chemical in soot –benzo(a)pyrene- is the same cancer-causing chemical found in cigarette smoke. While Percival Pott made the first association between cancer and the environment, there is lots of more recent evidence. This has been obtained from retrospective, epidemiological studies (i.e. the study of cancer incidence in persons previously exposed to a suspected environmental factor). These include: a) radiologists and X-ray technicians, b) survivors of atomic bombs and atomic accidents, c) survivors of chemical warfare, d) inhabitants of industrialized cities, and e) smokers and drinkers. In all cases, the incidence of cancer in the exposed group was significantly higher than those of the unexposed group.
The Role of Epidemiological Studies in Identifying the Factors that Cause Cancer
Having established that the environment and cancer incidence were causally related, scientists next asked what proportion of cancers are environmentally induced? The answer to this question was obtained from epidemiological studies involving the incidence of specific cancers in different parts of the world. In these studies, it was assumed that for any given cancer, the area of lowest incidence represents the proportion of that cancer arising from spontaneous mutation while the area of highest incidence represents the spontaneous rate plus the environment-induced rate. The difference between the two, calculated as a percentage, represented a conservative estimate of the proportion of cancers caused by factors in the environment. We now know that greater than 90% of all cancers induced by environmental factors and are thus theoretically preventable! Many environmental factors have been identified since 1950; however, they fall in three basic groups of cancer causing agents (i.e., carcinogens): physical agents (e.g., X-rays, UV radiation), biological agents (e.g., viruses and bacteria), and chemicals (e.g., benzene, dioxins, polycyclic aromatic hydrocarbons (PAHs)). [NOTE: Chemicals are believed to play a major role in greater than 80% of the environmentally induced cancers] Humans are exposed to these environmental factors as a consequence of certain behaviors (e.g., tanning, smoking), nutrition (water and food), occupation and lifestyle factors, to name a few. While a large number of risk factors have been identified, there is general agreement that diet and smoking play critical roles in the high cancer incidence and mortality rates in North America. [NOTE: There are in excess of 6000 chemical metabolites in cigarette smoke; 75 of these are proven cancer causing agents!]. So, what about Essex County?
Cancer in Essex County: Present Statistics and Future Perspectives
1. Where is the geography of Essex County?
Essex County comprises an area of about 1900 square km at the extreme tip of Southwestern Ontario. It is a peninsula bounded by Lake Erie, the Detroit River, Lake St. Clair and Kent County to the east.
2. What do we do?
Windsor is a major manufacturing center. In 1991 there were greater than 800 manufacturing plants making: a) cars and related products, b) machine tools, chemicals and plastics, c) pharmaceuticals, and d) food and beverage products. The commonest job categories for males are assemblage (17% of total jobs), and processing and machining (11%). The commonest job category for females is clerical work (29%); however 8% work in assembling, processing and machining. Essex County as a whole is an active agricultural area reflecting a wide range of crops and a substantial greenhouse industry. About 4% of males and 2% of females are classified as farmers. [NOTE: A person’s occupational environment has been implicated as a risk factor for cancer; much of this risk reflects the kinds of chemicals persons in that environment will encounter.]
3. What is the current and projected population and age structure of Essex County?
In 1991 the population of Essex County was 327,365; 262,075 lived in Windsor. A total of 76% live in urban centers, and 61% in Windsor proper. It has been estimated that the population of Essex County will increase by 17% by 2001, by another 13% by 2010, and by another 8% by 2020. If these trends are maintained, the population of Essex County will reach 483,000 by 2021.
The age distribution for Essex County is similar to trends in North America as a whole and demonstrates a "baby boomer" bulge. In 1991, 19% of the population was between 0-14 years of age, 44% between 15-44 years of age, 23% between 45 and 64 years of age, and 14% equal to or greater than 65 years of age. The largest group in 1991 was between 30-44 years of age (baby boomers). This group will begin entering the "cancer zone" (i.e., 50 years and older) by 2000. [The incidence of cancer as a whole increases exponentially after the age of 50. The highest incidences of cancers (i.e., peak incidences) of the colon, rectum, breast and prostate occur in the 65-74 year age group; those for lung cancer occur in the 50-64 year age group.] What does this mean? Essex County can expect a dramatic increase in cancer numbers between now and 2021.
4. What are the cancer statistics now?
Cancer statistics are approached from 2 perspectives: incidence and mortality. In general, incidence exceeds mortality; however, the relationship between incidence and mortality varies with respect to the type of cancer. For the most severe cancer sites (e.g., pancreas) incidence and mortality are essentially the same.
For both males and females, cancer incidence and mortality were second only to circulatory diseases. This is consistent with the Ontario, Canadian and North American trend. However, there are significant regional variations across Ontario both on gender-specific and cancer site-specific bases. Data compiled over a 10 year period (1976-1985) indicate that Essex County males fell in the highest quintile (i.e., top 1/5) of standardized mortality ratios (SMR) when considering all cancer sites. With respect to specific cancer sites, SMR for Essex County males during the 1975-1986 period fell in the highest or second highest provincial quintiles for most of the common sites including: tongue and mouth, pharynx, stomach, colon and rectum, liver, gallbladder, larynx, lung, connective tissue, melanoma of the skin, Hodgkin’s disease, and leukemia. The exception was the prostate which had SMR values in the fourth quintile. In the same period, SMR for Essex County females were not significantly different from provincial norms when considering all cancer sites or specific cancer sites.
To follow trends, an update analysis was carried out for the 1987-1991 period (Ontario Cancer Registry). These statistics demonstrate that for Essex County:
1) lung cancer incidence has increased in males and females, while mortality has increased in males
2) colorectal cancer incidence and mortality have increased in males and females
3) breast cancer incidence and mortality have increased in females
4) prostate cancer incidence and mortality have increased in males
5) stomach cancer incidence and mortality have decreased
.
With respect to specific cancer sites, SMR for Essex County males were greater than the provincial norms for: tongue and month, pharynx, colon and rectum, gall bladder, pancreas, liver, larynx, lung, melanoma of skin, prostate, testis, bladder, kidney, leukemia, bone and connective tissue. The SMR for Essex County males were less than the all-Ontario rates for: eye, small intestine, myeloma, Hodgkin’s and non-Hodgkin’s lymphoma, thyroid, central nervous system, lip, stomach and esophagus.
5. What risk factors are contributing to the high incidence and mortality scores in Essex County
males?
a) Socioeconomic status (SES): Cancer incidence and mortality show definite and complex linkages to SES. For example, it has been clearly established that the incidence of cancer is significantly higher in the unemployed and in single parents than their employed and double parent counterparts. It has been suggested that the higher incidences reflect increased stress and decreased time for attention to personal health. Historically, Windsor has been above the provincial and national levels for unemployment and single parenting. There has been a movement toward provincial norms during the last few years.
b) Education and Literacy: Cancer incidence and mortality appear to be linked to education and literacy levels. Once again this linkage is complex and may reflect the lack of "knowledge tools" to make important decisions concerning health, cancer prevention and so forth. Windsor scored below the Ontario average for four Education/Literacy criteria:
% of Total Population
Criterion Essex County Ontario
University education 19% 22%
less than grade 9 education 14% 12%
skilled readers 50% 62%
(i.e., can process instructions
newspapers, and so forth)
nonreaders (can’t read) 22% 17%
[NOTE: In 1996, greater than 25% of the Essex County people used computers and the internet. This has important implications for cancer since it provides an alternative means for communicating health-related information to a large number of people.]
c) Behavioral and Nutritional Habits:
i) Smoking: " The global health implications of smoking for Essex County are startling: 500 deaths and 80,000 hospital days annually are attributable to smoking. Smoking is directly associated with cancers of the lung (the major killer), the upper airway, the esophagus, the cervix and the bladder."
The number of smokers in Essex County exceeded the Ontario average (i.e., 34% versus 30%). This was true for all age groups in males, and for the 20-44 and 65+ year groups in females. The extent of smoking was correlated with occupation. The number of smokers was greatest in manual professions (i.e., 40%) and lowest in professional and technical professions (27%).
It has been estimated that 2400 Essex County young people between the ages of 12 and 17 commence smoking annually; 30-40% of these are destined to die from it before age 70. It was further estimated that 1155 years of life were lost for males and 483 years of life for females in Essex County during 1992. Considering comparisons of years of life lost across Ontario, it was found (1986-1992) that for Essex County males, lung cancer was 30% higher as a cause of early death than for the province as a whole; for Essex County females, lung cancer was 8% higher.
Smoking is also associated with circulatory diseases. For Essex County males heart disease was 8% higher than the province as a whole; for Essex County females, heart disease was 17% higher than the province as a whole.
ii) Nutrition: "Dietary fat intake has been associated with increased risks of colon/rectum cancers and with breast cancer." It has been suggested that this linkage reflects in part the accumulation of environmental contaminants in fatty tissue. These contaminants can induce cancer- causing mutations in the cells and ultimately lead to cancer in the individual.
Fat as a total percentage of energy intake in Essex County is typically above the recommended maximum of 30% of calories. More than 33% of the population obtains greater than 38% of their daily calorie intake from fat, while a startling 87% of the population have a high fat diet. Conversely, at least 60% of the population takes in less than the recommended 25 grams of fiber daily. These statistics are compounded by the facts that greater than 30% of the population is "medically" overweight and between 50-60% are inactive. Taken together, these nutritional behaviours favor the accumulation of cancer causing chemicals in the individual, and minimize their removal by metabolism and excretion.
d) Environmental Factors Affecting Cancer Risk in Essex County:
i) Location and Climate: " Exposure to UVB radiation from the sun is linked to increased incidences of cancers of the skin." Because of Essex County’s geography, its cumulative UVB readings are the highest in Ontario. If global trends in ozone depletion continue, this exposure will continue to rise. These conditions, in turn, can result in an increase in cancer of the skin.
ii) Great Lakes and Other Waters: "There is general consensus that the waters surrounding Essex County are contaminated with numerous chemicals that can directly or indirectly cause cancer; these include: polycyclic aromatic hydrocarbons (PAHs), polychlorinated biphenyls (PCBs) and halogenated aromatic hydrocarbons (HAHs)." This compounds are not water soluble so they bioaccumulate in the fat tissue of organisms living in the water. These levels become magnified (i.e., biomagnification) as you proceed up the food chain. For example, contaminated small fish are eaten by larger contaminated fish, then we eat the "doubly contaminated" larger fish.
iii) Urban Industrial Environment: "The environmental consequences of our own manufacturing industries are compounded by those of our closest neighbour, Detroit". Many of the environmental contaminants that are found in our air and water supplies can be traced to manufacturing and chemical production in Essex County and Detroit.
iv) Local Environment Air Quality: "The general air quality in Essex County is comparable to other urban areas in Ontario. A poor air quality reflects high levels of ozone, carbon monoxide and PAH contaminants that produced by the combustion of fossil fuels." It has been estimated that the lifetime cancer risk of "breathing" is from 5-95 cases per 100,000 individuals. This is hundreds of times lower than the cancer risk associated with smoking and with diet.
Bottom Line: In view of the statistics for Essex County, it has been estimated that 40% of Essex males and 30-33% of Essex County females will develop cancer. The value for males is greater than the 30-33% provincial norm.
6. What can be done???????????????????
Five areas have been targeted by Cancer Care Ontario:
a) prevention (e.g., improve diet, stop smoking, improve SES, etc.)
b) research/education
c) early detection/screening
d) treatment/clinical services
e) supportive care
Of these, preventative measures could have the greatest impact on current trends in cancer incidence and mortality. The extent of this impact depends entirely on the choices you make now.