MOLECULAR BASIS FOR CANCER
I. INTRODUCTION: CONCEPTS IN MOLECULAR PROGRESSION
OF CANCER
II. GENETIC ALTERATIONS IN CANCER
III. NON-GENETIC FACTORS IN CANCER
CANCER CAUSATION AND DEVELOPMENT
I. CANCER CAUSATION
II. CANCER DEVELOPMENT
III. CHEMICAL CARCINOGENESIS
IV. VIRAL CARCINOGENESIS
V. FOREIGN BODY CARCINOGENESIS
PATHOLOGY/BIOLOGY OF COLON CANCER
I. GENETIC ALTERATIONS IN MULTISTEP CANCER
II. THE GENETICS OF FAMILIAL COLON CANCER
KEYWORDS:
Keywords are in italics in the lecture notes.
OBJECTIVES:
POINTS OF INTEREST- Somatic defects in these genes are involved in cancer. What happens if a person has an inherited defect in one of of these growth regulatory genes??? IT DEPENDS on the gene. Defects in ras are probably not survivable during embryogenesis, leading to grossly abnormal growth of the embryo and spontaneous abortion. Defects in tumor suppressor genes normally lead to cancer predisposition syndromes, in which otherwise clinically normal persons have a high risk of developing cancer in their lifetime. Defects in growth factor receptors may or may not be survivable depending on the receptor. For example, persons born with a nonfunctioning androgen receptor will be clinically normal if 46(X,X), but 46(X,Y) karyotypic males will develop as clinically and anatomically normal females until puberty. Defects in growth factor receptors are likewise heterogeneous. Persons born with an abnormal fibroblast growth factor receptor type III (fgf3) will be affected by achondroplasia, the most common form of dwarfism and one of the most common autosomal dominant genetic disorders.
What happens if a person inherits a defect in one of these DNA repair pathways? Often, it appears that this causes a cancer predisposition in the carrier. Examples:
A critical role for cyclin-dependent kinases (termed cdks) has been preserved throughout eukaryotic evolution. However, in mammals, there are several cdks (at least 6) and a variety of cyclins (at least 10). The diagram below shows a greatly simplified schematic of cdk activity through the cell cycle. A critical question of interest is the nature of the specific substrates for the cdks at each transition during the cell cycle: For example, what are the substrates for cyclin E/cdk2 that regulate entry into the S phase? In the transition of G1, the retinoblastoma gene product has been shown to be a critical target for cyclin D/cdk4 activity. Indeed, the PRAD1 oncogene in breast cancer and the bcl1 oncogene in B cell lymphoma both encode D-type cyclins.
When functionally abnormal, which genes are able drive cells through the cell cycle? Normal cellular genes that contribute to cancer when functionally abnormal are called oncogenes. The normal counterpart of such a gene is called a proto-oncogene.
The central role of p53 and Rb in the regulation of cell growth is evident from the study of three unrelated DNA viruses that cause cancer in rodents and humans. SV40 (simian virus 40) transforms a number of cells in culture, including those of human origin, but does not cause cancer in humans. Adenovirus transforms rodent cells in culture, but has not been implicated in human cancers. In contrast, certain strains of human papilloma virus (e.g. HPV16, HPV18, and HPV33) have been implicated as one agent that contributes to the development of cervical cancer. These three viruses are evolutionarily unrelated, yet all three produce protein factors that inactivate the function of the Rb and p53 proteins. These viruses inactivate Rb and p53 in order to drive quiescent cells into the S phase, which creates a cellular environment conducive to viral replication. In certain instances, such as when the virus integrates into the cellular genome, cellular transformation is a byproduct of the induction of cell division by the viral oncoproteins.
p53 |
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SV40 |
T-antigen |
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Rb |
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Adenovirus |
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HPV |
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E7 |
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How does p53 act to regulate the cell cycle? Originally it was widely believed that p53 was a critical component of the cell cycle machinery. The creation of transgenic mice that lack p53 showed that this is not true: p53 knockout mice are viable and grow and develop normally, but develop malignancies in many tissues at a very early age. Subsequent studies show that p53 is a "guardian of the genome"; when cells sustain DNA damage, p53 undergoes a conformational change that activates the proteins' function as a transcription factor. p53 then induces the expression of genes that shut down the cell cycle until the DNA damage is repaired. The major gene product induced by p53 is WAF1/CIP1, a 21 kd protein that inactivates cyclin-dependent kinases that regulate transition through G1 and entry into the S phase. In this manner, damaged DNA is not duplicated. In some instances, p53 also participates in programmed cell death (apoptosis).
A Normal Cell Cycle G0 phase G1 S Growth induction Activation of cdk/cyclin complexes DNA replication
G0 phase G1 S Growth induction in the presence of damaged DNA Activation of p53; induction of WAF1/ CIP1 expression
Inactivation of cdk/cyclin complexesNo replication of damaged DNA
G0 G1 S phase Growth induction in the presence of DNA damage No activation of p53; no induction of WAF1/ CIP1 expression
Activation of cdk/cyclin complexesReplication of damaged DNA
A statistical analysis of the age of onset of retinoblastoma, a rare malignant tumor of the eye, led Knudson to formulate the "two-hit hypothesis" for the growth of retinoblastoma tumor cells. In contrast to gain-of-function mutations (such as those that occur in ras), Knudson proposed that both alleles of the RB gene had to suffer loss-of-function mutations in order for retinoblastoma to occur. Molecular analysis of the RB gene in retinoblastomas has proven that Knudson's theory is correct. Given that loss-of-function is required for the RB to influence cell growth, the RB gene was dubbed a tumor suppressor gene. pRb is expressed in all human tissues with about equal abundance, and is mutated a large spectrum of human malignancies, including small cell lung, bladder, and breast carcinomas, a number of sarcomas, and other tumor types. However, RB is not mutated in all human malignancies. Molecular cloning and analysis of RB function shows that RB is a member of a multigene family that includes at least two other members, p130 and p107.
A simple model for the action of Rb has been developed: In resting, senescent, or differentiated cells, Rb is largely unphosphorylated. In cycling cells, Rb becomes phosphorylated during G1, and is progressively phosphorylated during the S phase and G2/M. In G1, hypophosphorylated Rb protein binds E2F, masking its transcriptional activation domain, and required for entry into the S phase are not expressed. Upon induction of cell division, Rb becomes phosphorylated, and E2F is freed to activate the transcription of genes involved in DNA synthesis. If Rb is missing, or contains mutations that prevent it from binding to E2F, E2F inappropriately activates transcription of genes required for entry into the S phase. Thus, Rb can be considered a negative regulator of the cell cycle.
Note of interest: Cdk1 (the mammalian homolog of cdc2), cdk2, and cdk4/cyclin
D/E/A complexes stimulate pRb phosphorylation in vitro, and elevated expression
of cyclin D, A and E in cells can induce pRb phosphorylation. Since cyclin
D can physically associate with pRb, and cyclin D/cdk4 complexes are active
during G1, these cdk complexes are thought to be critical for the phosphorylation
events that inactivate the suppressive activity of Rb during G1. Thus, a
main target of cyclin D expression in cancer may be to phosphorylate pRB
(or related proteins), thereby overriding the growth suppresive activity
of pRB.
The association of pRb with E2F turns a positive transcriptional regulatory element into a negative elements by masking the transcriptional activation domain of E2F. In the simplest sense, phosphorylation of pRb releases pRb from E2F, unmasking its transcriptional activity and activating gene expression. Thus, when RB is missing, E2F activity is not inhibited in G1, and cells gain a growth advantage over their neighbors. Why isn't RB mutated in every tumor? Because certain cell types regulate growth through different pathways that may render RB less important in some tissues than others.
Unlike tumors in other species, relatively few human tumors are the direct result of oncogenic viruses.
Natural hormones or growth factors - whether endogenous or exogenous - may play a role in stimulating growth, cell division, and other events critical to the process of oncogenesis. They do not necessarily lead to mutation and are thus epigenetic.
Examples:
A wide diversity of biological, chemical, and physical agents have
the potential for inducing cancer in man. However, the majority of man's
common cancers have no recognized cause (breast and ovary in females, prostate
in males, brain and pancreas in both sexes). Many of these spontaneously-developing
cancers may result from the effects of endogenous mutagens, i.e. mutagens
that originate in the body, such as oxygen free radical.
Each of the various classes of agents known to induce cancer in man or animal
(naturally or experimentally differ; each has a different mechanism of action,
and the epidemiology and pathogenesis of the disease processes also differ.
Thus, an analysis of each of the individual causes of cancer is a perplexing,
complicated undertaking. Since in this course little time is available to
explore these issues in detail and discuss examples individually, we are
obliged to provide you generalization annotated by specific examples.
An enormous body of data accumulated from observations in humans and experiments
in animals indicate that host factors are critical to the development of
cancer. These involve a wide variety of genetic influences as well as factors
unique to the environment and lifestyle of the host. All of us experience
DNA injury on a continuous basis in both our somatic and reproductive cells.
Fortunately, this injury is usually repaired by natural mechanisms. When
it is not, a mutation occurs. The mutation may be silent, it may be lethal,
it could cause a developmental abnormality, or it could result in cancer.
Usually, however, several mutational changes must accumulate in the cell
genome for cancer to develop. Factors related to host susceptibility may
determine whether or not disease develops. One can look at this possibility
optimistically or pessimistically. From a pessimistic perspective, the notion
that we all experience DNA changes which could result in clinical cancer
is frightening. From an optimistic perspective, we can accept the fact that
cancer occurs uncommonly, whereas DNA damage is an everyday event. I am
an optimist. I believe the potential for preventing or reversing cancer
in man is ever present if we only understood its cause.
In this session, we will overview the mechanisms whereby DNA changes can
lead to cancer providing specific examples as to how this occurs. We will
also overview the host factors which influence the development of the disease.
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Cancer deveops when critical changes in the DNA of cells results in their loss of responsitivity to nornal cellular control mechanisms.
The loss of SUPPRESSOR genes from cells by these mechanisms may be one of the key factors allowing cancer to develop and progress.
The above concepts are undergoing continuous re-evaluation in epidemiological studies conducted in large population groups. The findings in these studies conflict. Clearly, the role of these and other nutritional factors in neoplasia is far from clear.
Dramatic differences in the prevalence of cancer exist between populations residing in various regions of the world. While host factors other than nutrition and heredity may be important considerations, the actual explanation is lacking. In the accompanying table, note the differences between Japanese and North American residents and the changes that occur in 1st, 2nd and 3rd generation Japanese immigrants.
When I was an intern, it was common to treat hyperthyroidism with a radioactive thyroid hormone A BETA RAY EMMITTER. In the central pacific in the 1950's, atomic bomb tests to evaluate new weapons and these explosions often yielded an exceptionally large amount of radioactive iodine which occasionally contaminated the food of nearby islanders. The end result of all these exposures has been the occurrence of cancer of the thyroid gland related to the accumulation of radioiodine in the tissue, derived from contaminated water and food. When I was in my teen's, friends with severe acne were treated with X-RAY. Now, these same people are developing thyroid nodules and may be at risk for developing thyroid cancer.
Radium is an abundant producer of alpha particles, very powerful rays that have a short radius of effect, but a considerable capability to damage cellular DNA. Years ago, it was popular to paint the numerals on a wrist watch with radium so that the numerals would glow at night. The trade was centered in Waterbury, Connecticut. It employed a large number of women who had dexterity and the patience to hand paint the numerals on wrist watch faces. Camel hair brushes were used. The workers would moisten the brush with their saliva, dip it into the paint and then paint the numeral. In this way, they would absorb a great deal of radium containing dye into their system in an unrecognized manner. Many years after these women began their work, they began to develop bone cancer. It turns out that radium is a bone seeking element and deposits at sites of bone metabolism. With it, of course, comes the radiation so that localized areas of bone were bombarded with high concentrations of ALPHA PARTICLES. The end result was an osteosarcoma or fibrosarcoma of bone. Obviously, this practice has ceased, but not until a long latency period for the cancers that evolved and a large number of individuals were affected.
Radon in the home is now a concern, for we breathe it in, and the alpha rays can damage the DNA of the cells that line the bronchial tree. In Uranium mines of the Southwest, radon gas exposure is exceedingly high, and these men have been shown to develop lung cancer. Cigarette smoking turns out to be a cofactor.
Epidemiological studies on atomic bomb victims exposed to GAMMA and X-RAYS, radiologists who used X-RAY radiation casually in their work, and persons exposed to diagnostic radiation in utero or in early infancy have shown an increased prevalence of leukemia occurring in these persons. The findings correlated well with studies in experimental animals which demonstrate the same phenomena. In general, leukemia as a result of irradiation has a relatively long latency period.
Points to Emphasize in your thinking:
The concept of chemical carcinogenesis was first introduced to medical science
during the industrial revolution. In that era, residential and industrial
building heating was primarily provided by coal fires. As a result, large
numbers of chimney sweeps were required to remove the carbon from the chimneys
of buildings to reduce the hazard of chimney fires. Tall, narrow, chimneys
required small people who could slide down the chimney, so homeless waifs
were often recruited for the job. The youngsters slide down the chimneys
scraping off the accumulated carbon in the process. Sir Percival Potts,
a surgeon, noted that many of these young men developed "warts"
on the scrotum and later warts of this type sometimes became invasive cancers.
He associated their work with the development of the "warts" and
concluded that the soot in the chimneys was responsible. Innovatively, Potts,
provided an opportunity for these youngsters to bath routinely so that the
soot would not accumulate in the corrugated skin of the scrotum. As a result,
the prevalence of warts decreased substantially, fulfilling Koch's hypothesis.
We know now that coal soot contains coal tar that is comprised of a large
number of complex hydrocarbons including the polycyclic aromatic hydrocarbons.
The basic precursor chemicals are found in coal, wood and petroleum where
there are not carcinogenetic, but after incineration at elevated temperatures
the noncarcinogenetic chemical are converted to carcinogens, i.e., they
are active carcinogens upon metabolism in epithelial cells on the surfaces
of the respiratory tract. Humankind now are exposed to these polycyclic
aromatic hydrocarbons in PETROLEUM PRODUCTS, COAL EFFLUENTS such as those
from coke ovens, and cigarette smoke.
Everyone knows that cigarettes are the major cause of bronchogenic carcinoma
(lung cancer). The mechanisms are clearly outlined in your book. You should
have in mind a very specific knowledge as to how the polycyclic aromatic
hydrocarbons in cigarette smoke are transformed to electrophils by CYTOCHROME
P450 MONOOXYGENASE, the ELECTROPHILS then have the ability to form adducts
on the DNA and ultimately to cause DNA damage. This is discussed in your
text. I will discuss smoking and disease in the Environmental Pathology
lecture.
Bronchogenic carcinoma is an example of MULTISTAGE CARCINOGENESIS in which
multiple cumulative chemical injuries to the cells of the respiratory tract
ultimately result in cancer. It introduces the concept of the initiator
and the promoter of cancer. In this concept, the polycyclic aromatic hydrocarbons
are the initiator of DNA injury but many additional chemicals in the cigarette
smoke stimulate cell proliferation and increase sensitivity to the carcinogenic
initiator.
Please become acquainted with the INITIATOR or PROMOTER concept by reading
the book. I'll discuss it briefly.
For years, we have known that cancer of the liver occurs commonly in Sub-Sahara Africa, and throughout the Far East.We have also known that a chemical carcinogen termed "Aflatoxin" is frequently found in the diet of individuals in these areas. AFLATOXIN is produced by a fungus of the genus Aspergillus. It contaminates peanuts and a variety of other foods grown in these parts of the world. Aflatoxin is known to produce cancer in the livers of turkeys and presumably, it plays a role in the cancer in humans. But definitive proof has been lacking. Approximately 15 years, HEPATITIS B turned out to be a new possible cause of liver cancer. This is a small DNA containing agent which can integrate with the cellular DNA in the liver viral during replication. It apparently is carcinogenic in isolated cell culture systems and similar viruses produce liver cancer in ground hogs and in ducks. Thus, a role for hepatitis B virus in the genesis of cancer of the liver has evolved. But how do you prove it? And does it rule out the aflatoxin hypothesis? We just don't know. A common theory relates to the fact that hepatitis B virus and aflatoxin may work as cocarcinogens in the causation of HEPATOCELLULAR CARCINOMA. The question is not trivial since worldwide, hepatocellular carcinoma is one of the commonest forms of cancer of human mankind.
Many years ago, ANILINE AND AZO CONTAINING DYES were commonly used to color clothing. They were the "gold standard" for color rendition. It was then found that workers in the factories where aniline dye was made or used developed an inordinate number of bladder cancers. These compounds are carcinogenic in animals and appear to be carcinogenic in the humans utilizing them. Now these dyes are excluded from the market and there is no longer an association between bladder cancer and the manufacturing and staining of clothing. However, epidemiological studies have established a relationship between urinary tract cancer and cigarette smoking.
Shortly before the turn of the century, several cases of fatal aplastic anemia occurred among workers in a tire factory. Some 30 years later, a case of acute lymphoblastic leukemia attributable to BENZENE exposure was described. The clinical and epidemiological association of bone marrow depression followed by acute leukemia consequent to benzene is now well established. In the majority of cases, the leukemia is of the acute myelogenous type and occurs with a latency period from 5 to 20 years after exposure.
BENZENE (C6H6) is one of several aromatic hydrocarbons found in crude and refined petroleum products. It is extensively used as an intermediary in bulk and specialty chemical production and as an industrial solvent. In low concentrations, benzene is present in fruit and vegetable products and in cigarette smoke. Thus, it is universally found in our modern industrialized environment and is an exceedingly common indoor contaminant to which most of us are exposed chronically. However, overt toxicity (such as aplastic anemia) is not demonstrable at the exceedingly low ambient concentrations experienced by the great majority of those who are exposed environmentally.
Epidemiological investigations to assess the hematological effects of benzene have been difficult to conduct because of the sporadic and infrequent occurrence of leukemia among those who experience long-term, relatively heavy exposures in industry. Regulatory efforts have had a substantial effect on the benzene concentrations now found in most occupational settings and current regulations restrict the amounts in ambient air to no greater than 1 ppm. Exposure to aromatic hydrocarbons other than benzene in various industries is an ongoing concern because of the difficulties of accessing possible risks to hematopoietic tissues.
Although the oncogenic properties of various salts of heavy metals have long been recognized, the pathogenic mechanisms involved in carcinogenesis are incompletely understood. The subject proves exceedingly complex, in part because of the many significant gaps in the epidemiological and experimental information. Confusion also relates to the different forms of these metals found in our environment and variables in human exposure to the various chemical analogues of the metals.
The development of skin cancers among patients being treated with ARSENICAL compounds for various dermatological conditions was first described in 1888. Subsequently, similar lesions of the skin were noted to occur among members of certain occupational groups exposed to arsenic either by direct skin contact or by the respiratory route, or after ingestion of therapeutic agents. For unknown reasons, these lesions exhibited a unique and pathognomonic distribution pattern on the palmar and plantar surfaces, the scrotum, and the nipple. In the early 1900s, cases of lung cancer attributable to industrial exposure to chromium and arsenical compounds were first described. Later, epidemiological investigations established an association between employment in the metal smelting industry and respiratory tract cancer. The specificity of the link between lung cancer and smelter effluents containing NICKLE salts has been obscured by the chemical complexities of the by-products of smelting and the commonality of cigarette smoking among the exposed blue-collar workers. CHROMIUM miners have similarly experienced a high medicine of lung cancer which has now been attributed to direct exposure to certain chromium salts.
The concept of multistage carcinogenesis implies that cells sustain superimposed mutational events and clonal selection in the process of transformation. Thus, the likelihood that an initiated cell will ultimately develop into a malignant neoplasm is dependent on clonal expansion and the probability that additional mutations will be superimposed upon the progeny. Cells proliferate in response to either cytotoxic injury or mitogenic stimulation. Cytotoxicity leads to cellular regeneration. In this context, there is good reason to believe that leukemogenesis consequent to bone marrow irradiation or benzene exposure could, in whole or in part, be a reflection of endogenous mutagenic events occurring during regeneration of the marrow elements under the influence of hematopoietic growth factors.
Mitogenesis resulting from chemical exposures can be a receptor-mediated event, acting through secondary messengers that regulate cell replication. Because all chemicals prove cytotoxic at some dosage, albeit in unphysiologic amounts, the influence of dosage, uptake, transport, and metabolic activation are key considerations in assessing the cytotoxicity of an environmental chemical as a promoter of carcinogenesis in humans. Ethanol, when consumed in excess, and carbon tetrachloride, resulting from chronic occupational exposure, are examples of hepatoxic chemicals that stimulate cell multiplication in the liver and may promote carcinogenesis by this mechanism. Hepatitis B infection is another specific agent that potentially contributes to neoplastic transformation of the liver as a result of chronic cytotoxic damage to this organ.
Several mitogenic chemicals of considerable environmental importance have been found to be highly carcinogenic in rodent assays but are not metabolized to carcinogens in vivo and lack the ability to bind DNA covalently. Of these, DIOXIN is the most notable and toxic member of a group of structurally similar compounds that includes biphenyls, furans, and many other isomers too numerous and too chemically complex to summarize here. The ubiquitous nonbiodegradable environmental contaminant, dioxin, is a by-product of the manufacturing and use of halogenated aromatic compounds such as the phenoxy herbicide, Agent Orange. In contrast, POLYCHLORINATED BIPHENYLS were widely produced in industrialized countries for use as a fluid insulator and fire retardant until they were banned by governmental action in 1977.
Human bioavailability from the many potential environmental sources (primarily air and foods) is poorly defined, but storage in body adipose tissue is inevitable because of the lipid solubility of these compounds. The biologic half-life of dioxin in human tissue is uncertain but is variously estimated to be from 3 to 8 years. All of us have within our adipose tissue low concentrations of a variety of chlorinated hydrocarbons, and those who have been exposed to these chemicals occupationally have substantially greater concentrations in their body fat. Because dioxin is not mutagenic, the effects of these compounds would appear to be promotional. Although concern is voiced repeatedly regarding the potential carcinogenicity of the large family of chlorinated hydrocarbons, as of yet, epidemiological evidence has not accumulated, demonstrating an increased prevalence of cancer in environmentally exposed humans.
An enormous body of epidemiological and experimental evidence has established a role for estrogens in the pathogenesis of cancer of the female breast and the endometrium. In addition, synthetic exogenous estrogen administration during pregnancy is strongly associated with the development of vaginal adenocarcinoma in female offspring and possibly germ cell tumors of the testes in male children. Estrogens play a role in the replication of cells of the mammary gland and counteract the effects of progestational hormones in the endometrium. Thus, by stimulating cell growth in target tissues, these compounds can enhance susceptibility to exogenous and endogenous carcinogens or increase the likelihood of replicative errors in the DNA of these estrogen- sensitive tissues.
A wide variety of chemical compounds in our environment manifest properties that mimic the estrogenic effects of hormonal estrogens when evaluated in animals. These compounds have exceedingly weak estrogenic effects in humans and their disease causing potential is obscure. One commonly recognized, ubiquitous chemical of this type is dioxin, already mentioned above. It is carcinogenic in animals, but its role in humans is uncertain.
Points to Emphasize in Your Thinking:
LEUKEMIA AND LYMPHOMAS occur in approximately 1% of the general population.
As noted above, the prevalence of these diseases is increased in individuals
exposed to excessive concentrations of irradiation (atomic bomb victims)
and certain chemicals, including chemotherapeutic agents used to treat solid
tumors such as Hodgkin's disease.
Leukemia and lymphoma develop in experimental animals exposed to a variety
of different retroviruses (oncornaviruses). These agents act by the mechanism
of reverse transcriptase introducing through their RNA new genetic information
into the DNA genome of the host. Many (if not all) species of animals are
infected with retroviruses and many of these viruses now carry oncogenes
(which may play a role in cancer) acquired as protooncogenes from normal
cells.
The role of RETROVIRUSES in human leukemia has become apparent in recent
years with the appearance of HTLV-1, the cause of T-CELL LEUKEMIA. This
virus is endemic in Southern Japan and the Caribbean basin where it sporadically
causes lymphomas by mechanisms that are obscure.
Burkitt's lymphoma is a unique malignancy of children, which is prevalent
in the highlands of East Africa. It comprises about 1% of the lymphomas
occurring in children in this country and the rest of the western world
today. The tumor biology is intimately related to infections with EPSTEIN-BARR
(EB) virus, a member of the Herpesvirus group. In East Africa, youngsters
almost invariably develop the disease before the age of 10. They exhibit
massive tumors having a unique morphology, particularly in the mandible
of the face, and in females in the ovaries. These are unusual locations
for lymphomas in children. Invariably, the youngsters have antibodies to
EB virus. EB virus plays a role in tumor pathogenesis, but the mechanism
is obscure. While no one is certain as to why these lymphomas cluster in
East Africa, several considerations are relevant. Firstly, there may be
genetic factors that play a role. Secondly, this is an area of hyperendemic
malaria, and it is believed that chronic parasitism of EB infected children
stimulates the immune system and the proliferation of lymphocytes which
are in some way transformed by a virus. Finally, there is a specific chromosomal
translocation which implants the Ab oncogenes adjacent to the genes for
immunoglobulin production. Amplification of these latter genes and their
effect on immunoglobulins in the cells that produced them (B-cells) is thought
to be the means whereby the disease process occurs. If all of this sounds
confusing, it is because all of the elements have not yet been fitted together
into a clearly defined hypothetical pathogenetic construct.
Herpesviruses of other types have been shown to play a role in carcinogenesis.
The most common is a leukemia of chickens (Marek's disease), one of the
most devastating epidemic virus infections of commercial flocks of chickens
in this country. Up until a few years ago, Herpesvirus type II was thought
to play a role in carcinoma of the cervix.
Carcinoma of the cervix is one of the commonest and most deadly of cancers affecting women. It has long been recognized that a certain subset of the female population develops this form of cancer, whereas other women seemingly are resistent. The cancer has been associated epidemiologically with sexual activity early in life and multiple sexual partners. There is an exceedingly high incidence of cervical carcinoma among prostitutes, whereas the disease almost never occurred among nuns. Thus, venereal transmission of a carcinogenic agent was long suspected. Some 50 years ago, the smegma, a secretion of the foreskin of the male external sex organ, was thought to be a chemical that might cause cervical carcinoma as a result of direct contact. This concept was never widely accepted, but it was thought to be an explanation for the low prevalence of the cancer in Jewish women. Herpes viruses also were implicated. Twenty five years ago, the medical literature was replete with the notion that Herpes viruses transmitted sexually were the cause of carcinoma of the cervix. The concept fitted the epidemiological information, but alas it has proven to be wrong. Now we consider the papilloma viruses as the probable cause, but they do not seem to be the exclusive answer. Something else is required but medical science has not identified it .
Cancers of the glans penis are very rare, but in inhabitants of certain under developed parts of the world, they occur commonly. The prevalence of carcinoma of the glans penis is correlated with circumcision. The concept of male genital cleanliness thus is a consideration, but more modern thinking also incorporates the PAPILLOMAVIRUS in the concept. Interestingly enough, papilloma viruses are a major problem for females, but usually they are a minor annoyance for males. If they cause carcinoma of the glans penis, they must do so rarely since the disease in our western society is exceedingly common even though a substantial number of sexually active females have active papilloma virus infections.
Carcinoma of the anus was a rare disease prior to the sexual revolution of the 1960's. Now the cancer occurs commonly particularly in homosexual males. All of the existing evidence indicates that the anal carcinomas are due to papilloma virus. It is thus interesting that the glands penis is rarely affected whereas the anus is commonly affected as a result of sexual activity. This paradox has not been explained.
A number of different papillomavirus types infect the genital tissue of men and women. They occasionally are etiologically associated with penile and anal cancers in men, particularly those with indiscriminate sexual practices. In women, certain papillomaviruses are believed to be etiologically related to condylomas (venereal warts) of the vulva and dysplasia, carcinoma in situ, and invasive carcinoma of the cervix. This story is complex, and we can only touch on the highlights; specifically, warts are caused by several different papillomavirus types, particularly 1 and 5, vulvar condylomas are associated with types 6 and 11, and carcinoma of the cervix with types 16 and 18. Thus, the various lesions are type specific. Warts and condylomas are benign papillomatous proliferations superficially resembling tumors, but are not malignant tumors. Dysplasias and carcinoma in situ of the cervix are relatively benign, but at a certain point, carcinoma in situ may become an invasive cancer. Interestingly enough, the intact viruses can be demonstrated in CONDYLOMA and in CARCINOMA IN SITU as well as in dysplastic epithelial cells of the cervix, but after invasion occurs, the genome of the virus is integrated and infectious virus disappears. While the circumstantial evidence relating these viruses to carcinoma of the cervix is compelling, a cause and effect etiological relationship has not yet been established. In part, this relates to our inability to grow the viruses in the laboratory.
Points to Emphasize in Your Thinking:
In 1960, an inquisitive pathologist and epidemiologist discovered that asbestos, of the amphibole type, is associated with malignant mesotheliomas, an exceedingly rare form of tumor of the pleura. Since that time, countless Americans have developed mesotheliomas and died as a consequence of asbestos exposure. These unique tumors spread in the pleural cavity of the lung of individuals and expand to encroach upon the lung until the individual suffocates. Rarely they metastasize. Occasionally, malignant mesotheliomas occur in the abdominal cavity. The mechanisms whereby asbestos causes mesothelioma remains to be defined.
Schistosoma hematobium is an exceedingly common parasitic infestation of the venules of the urinary bladder in individuals residing in certain parts of Africa and Asia. As a result, the eggs are deposited in the walls of the urinary bladder where they fester and cause a granulomatous response. This irritates the mucosa of the bladder resulting in a hyperplasia of the transitional epithelium of the bladder. Occasionally it becomes malignant, resulting in squamous cell carcinoma. There is a strong association of cigarette smoking with urinary tract carcinomas in those who live in the western world. In endemic areas of Schistosomiasis, there may also be the superimposed effect of a chemical carcinogen which is excreted through the urine. We just don't know.
In addition to your text, a recent book "The Pathology of Environmental
and Occupational Disease" ed. J.E. Craighead addresses the issues discussed
in this section in a chapter on Carcinogenesis (Chapter 26). Copies are
on reserve.
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KEYWORDS:
Keywords are in italics in your lecture notes
OBJECTIVES:
Our understanding on the progression of nonhereditary cancers has been greatly
furthered by our study of families with excess cancer. In particular, several
syndromes related to familial colon cancer predisposition have been defined
clinically and are now understood at the molecular level. These are discussed
in the assigned reading by Lynch et al. All evidence so far indicates that
the type of tumors that occur in familial forms of cancer are no different
than those that occur sporadically. It is only the frequency with which
these occur that is different. Likewise, at the molecular level, there appears
to be a common sequence of events that occurs in familial colon cancer and
sporadic colon cancer. The principle differences between these two is that
all cells in the colon of a cancer-prone individual are in an activated
"premalignant" state (remember the discussion of field effect
from the previous lecture). The probability of these cells becoming malignant
is much higher than that in noncarriers. This is also the reason that cancer-prone
individuals often develop many different independent primary tumors.
Some important points to ponder:
Neoplasia I: Introduction to Neoplasia
Neoplasia III: Moelecular Aspects
of Neoplasia in Hematology
Questions?
Comments? Send a message to the CATS guru: jkessler@salus.uvm.edu
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