Neoplasia
Neoplasm is an asing mass of tissue as a result of neoplasia. Neoplasia (new growth in Greek) is the asing proliferation of cells, it is a widespread and potentially grave growth abnormality (dystrophic proliferation). The growth of this clone of cells exceeds, and is uncoordinated with, that of the normal tissues around it. It usually causes a lump or tumor.
Cancer is a disease of growth, division and cell differentiation, it is the result of mutation of genes controlling these processes (protooncogenes and cancer suppressor genes).
Cancer is synonymous with malignant tumor; the Latin cancer is actually a literal translation of the Greek karkinos for crab, a common creature on Mediterranean shores. In the Hippocratic books, karkinos and karkinoma are used for conditions that we would almost certainly call carcinoma (epithelial cancer) or, more generally, cancer. There seem to have been many reasons for borrowing the image of the crab, and the choice was extraordinarily successful: the name of the innocent crustacean has become a sinister metaphor, even for the destructive ills of society
Tumor is a typical pathologic process characterized by irregulated limitless growth of the tissue, which is not connected with the general structure of the impaired organ and its functions.
Tumor is growing from itself, i.e. it grows as a result of reproduction of even one malignant cell. The tissue of tumors differs from the original one by structure, physical and chemical, biochemical, functional and other signs. It is called atypism. These changes indicate anaplasia that is returning of the cell to its embryonic state and also metaplasia — acquisition of properties of other tissue.
Table 21. Epidemiology of human cancer
| Male | Female | ||
| most common (by occurrence) | most common (by mortality) | most common (by occurrence) | most common (by mortality) |
| prostate cancer (25%) | lung cancer (31%) | breast cancer (26%) | lung cancer (26%) |
| lung cancer (15%) | prostate cancer (10%) | lung cancer (14%) | breast cancer (15%) |
| colorectal cancer (10%) | colorectal cancer (8%) | colorectal cancer (10%) | colorectal cancer (9%) |
| bladder cancer (7%) | pancreatic cancer (6%) | endometrial cancer (7%) | pancreatic cancer (6%) |
| non-Hodgkin lymphoma (5%) | liver & intrahepatic bile duct (4%) | non-Hodgkin lymphoma (4%) | ovarian cancer (6%) |
Cancer is a global problem, and with reference to the globe, it is also a spotty problem. By definition, the task of epidemiology is to explain why a particular patient developed a particular disease at a particular time and place. Its ultimate goal is to find all causes of all diseases and to suggest preventive measures for every one.
The two basic rules of cancer epidemiology are that all types of cancer can occur everywhere, and that the incidence of each type varies from place to place. The lowest incidence of a particular cancer observed anywhere on the globe is taken to represent the baseline for that cancer, which is due to shared genetic and/or environmental factors. Any higher incidence is interpreted as reflecting some special local cause, usually environmental. This rule has been exploited for detecting causes in high-incidence populations.
We should recall here that incidence is the number of new cases in a population during a given period. Prevalence is the number of existing cases at a given time.
1. Types of tumors
When discussing human tumors, we will use the traditional distinction between benign tumors (slowly growing, noninfiltrating, not fatal) and malignant tumors (more rapidly growing, infiltrating, metastasizing, and if untreated fatal). When discussing experimental carcinogenesis, we will follow the party line of the experts: tumors are malignant or on the way to malignancy.
A benign tumor is a tumor that lacks all three of the malignant properties of a cancer. Thus, by definition, a benign tumor does not grow in an unlimited, aggressive manner, does not invade surrounding tissues, and does not metastasize. Common examples of benign tumors include moles and uterine fibroids.
The term "benign" implies a mild and nonprogressive disease, and indeed, many kinds of benign tumor are harmless to the health. However, some neoplasms which are defined as 'benign tumors' because they lack the invasive properties of a cancer, may still produce negative health effects. Examples of this include tumors which produce a "mass effect" (compression of vital organs such as blood vessels), or "functional" tumors of endocrine tissues, which may overproduce certain hormones (examples include thyroid adenomas, adrenocortical adenomas, and pituitary adenomas).
Benign tumors typically are encapsulated, which inhibits their ability to behave in a malignant manner. Nonetheless, many types of benign tumors have the potential to become malignant and some types, such as teratoma, are notorious for this.
Malignant neoplasm or malignant tumor: synonymous with cancer.
Table 22. Summary of features differentiating benign and malignant
neoplasms.
neoplasms.
| Feature | In Benign Tumors | In Malignant Tumors |
| Rate of growth | Slow | Fast |
| Mode of growth | Expansile | Infiltrative |
| General effects | Uncommon (except endocrine) | Common |
| Metastases | No | Common |
| Recurrence after removal | Rare | Common |
| Gross: | | |
| Capsule | Common | Pseudocapsule |
| Necrosis | Rare | Common |
| Ulceration | Rare | Common |
| Microscopic: | | |
| Atypia | Mild | Severe |
| Pleomorphism | Mild | Severe |
| Mitoses | Few | Many |
| Nuclear/cytoplasmic ratio | Normal | Increased |
| Nucleolus | Normal | Prominent |
| Ploidy | Often normal | Usually abnormal |
Methods to quantify the probable clinical aggressiveness of a given neoplasm and to express its apparent extent and spread in the individual patient are necessary for comparisons of end results of various forms of treatment.
The grading of a cancer attempts to establish some estimate of its aggressiveness or level of malignancy based on the cytologic differentiation of tumor cells and the number of mitoses within the tumor. The cancer may be classified as grade I, II, III, or IV, in order of increasing anaplasia.
Staging of cancers is based on the size of the primary lesion, its extent of spread to regional lymph nodes, and the presence or absence of metastases. Two methods of staging are currently in use: the TNM system (T, primary tumor; N, regional lymph node involvement; M, metastases). In the TNM system, T1, T2, T3, and T4 describe the increasing size of the primary lesion; N0, N1, N2, and N3 indicate progressively advancing node involvement; and M0 and M1 reflect the absence or presence of distant metastases.
3. Etiology and pathogenesis
Risk factors
Some mistakes in DNA replication throughout a lifetime are inevitable. However, certain conditions or behaviors, known as risk factors, can increase or decrease the likelihood of a mutation arising and a mutated cell being promoted until it is cancerous.
Geographic variations in the overall incidence of cancer and in the incidence of specific types of cancer also occur from one country to another, from one city to another, and from urban to rural areas. Detailed epidemiologic case control studies have sometimes uncovered associations with high-risk occupations, diet, environmental carcinogens, or endemic viruses; other occurrences remain unexplained. For example, the high incidence of stomach cancer in Japan has been related to diet (smoked raw fish). This type of cancer does not appear to be genetically determined, because Japanese emigrating to the United States show within a single generation the lower incidence of stomach cancer demonstrated by native-born Americans.
Behavioral risk factors. Certain behaviors increase the likelihood that an individual will be frequently exposed to cancer-causing stimuli. Behavioral risk factors include cigarette smoking and diets rich in animal fat and preserved meats. Approximately a third of all cancers can be attributed to cigarette smoking, and a third to diet. Obesity also may be an independent risk factor for cancer because of the increased accumulation of fat-soluble toxins and potentially carcinogenic hormones in fatty tissue. Even a low level of alcohol consumption is linked to an increase in breast cancer, as is a sedentary lifestyle. Other behavioral risk factors include those associated with secual behavior. A high number of secual partners and an early onset of secual activity increase the risk of becoming infected with the human papilloma virus (HPV), which is associated with genital neoplasms, and the AIDS virus, which is associated with Kaposi's sarcoma.
Hormonal Risk Factors. Estrogen may act as a promoter for certain cancers, such as breast and endometrial cancer. Because estrogen levels are high in menstruating women, the risk for developing breast cancer is increased in women who started menstruating early and reached menopause late. Delayed childbearing or choosing not to bear children increases the risk of breast cancer. Estrogen replacement therapy in postmenopausal women appears to be associated with an increase in the risk of breast cancer.
Inherited Risk Factors. A family history of cancer, especially clustered as one type, is a risk factor for developing cancer. Genetic tendencies for carcinogenesis may involve fragile or mutated tumor suppressor genes, susceptibility to certain mutagens or promoters, faulty proofreading enzymes, or a poorly functioning immune system. Inherited defects in the p53 gene have been documented to be associated with a high risk of cancer. Certain cancers have a higher tendency to run in families than others. For example, although most cases of colon cancer arise spontaneously, some families carry mutations that increase the risk of this disease.
Pediatric cancers likely have a genetic component. In children, the development of cancer is accelerated from several decades to only one or two decades. Acceleration may occur if a child inherits in the germ line (egg or sperm) one defective gene controlling a tumor suppressor or proto-oncogene product or develops such a mutation early in embryogenesis. Later, a second gene error would cause early cancer growth. Similarly, inheriting defective genes for proofreading enzymes would increase the risk of early cancer development.
History of Associated Diseases. Perhaps the most important finding in the history of a patient with suspected cancer is a record of diagnosis or treatment of previous cancer which greatly increases the chances that the current illness represents either a metastasis or a second primary tumor. Statistics show that patients who have had cancer—have a much higher incidence of a second cancer, particularly in the same tissue. For example, cancer in one breast increases the chances of cancer in the opposite breast. Second cancers of a different type—particularly leukemia and sarcomas—also occur as a complication of chemotherapy and radiation used to treat the first cancer.
In addition, certain disorders that in themselves are nonneoplastic carry an associated higher risk of development of cancer and are considered preneoplastic diseases. These diseases are uncommon, but together they constitute a significant group of risk factors
Table 23. The preneoplastic diseases
| Nonneoplastic or preneoplastic condition | Neoplasm |
| Down Syndrome (trisomy 21) | Acute myeloid leukemia |
| Xeroderma pigmentosum (plus sun exposure)- | Squamous cancer of skin |
| Gastric atrophy (pernicious anemia) - | Gastric cancer |
Factors that are protective against cancer development
Studies suggest that women who breastfeed for at least 6 consecutive months have a reduced risk of developing breast cancer. In addition, women who have had multiple pregnancies have a reduced risk of breast cancer. Progesterone is high during pregnancy and appears to be protective against breast cancer by inhibiting the stimulatory effects of estrogen.
Dietary factors are important in reducing cancer risk. Diets rich in substances known to scavenge or remove dangerous free radicals, called free-radical scavengers or antioxidants, may reduce the risk of certain cancers. These substances include vitamins A, E, and C and folic acid, all of which are prevalent in green, leafy and colorful vegetables and fruits.
Mechanisms of gene activation & inactivation
Cancer is a diverse class of diseases which differ widely in their causes and biology. Any organism, even plants, can acquire cancer. Nearly all known cancers arise gradually, as errors build up in the cancer cell and its progeny.
Anything which replicates (our cells) will probabilistically suffer from errors (mutations). Unless error correction and prevention is properly carried out, the errors will survive, and might be passed along to daughter cells. Normally, the body safeguards against cancer via numerous methods, such as: apoptosis, helper molecules (some DNA polymerases), possibly senescence, etc. However these error-correction methods often fail in small ways, especially in environments that make errors more likely to arise and propagate. For example, such environments can include the presence of disruptive substances called carcinogens, or periodic injury (physical, heat, etc.), or environments that cells did not evolve to withstand, such as hypoxia (see subsections). Cancer is thus a progressive disease, and these progressive errors slowly accumulate until a cell begins to act contrary to its function in the animal.
It has been suggested that neoplastic transformation occurs as a result of activation (or derepression) of growth promoter genes (proto-oncogenes) or inactivation or loss of suppressor genes. Activation is a functional concept whereby the normal action of growth regulation is diverted into oncogenesis. The resultant activated proto-oncogene is referred to as an activated oncogene (or a mutant oncogene, if structurally changed), or simply as a cellular oncogene (c-onc). Activation and inactivation may occur through several mechanisms: (1) mutation, including single nucleotide loss (frameshift) or substitution (nonsense or missense codon), codon loss, gene deletion or more major chromosomal loss; (2) translocation to a different part of the genome where regulatory influences may favor inappropriate expression or repression; (3) insertion of an oncogenic virus at an adjacent site; (4) amplification (production of multiple copies of the proto-oncogenes), which appear as additional chromosome bands or extra DNA fragments (double minutes); (5) introduction of viral oncogenes; or (6) derepression (loss of suppressor control).
Carcinogens
An agent that causes neoplasms is an oncogenic agent; an agent causing a malignant neoplasm (cancer) is a carcinogenic agent. Carcinogens are substances that are known to cause cancer or at least produce an increased incidence of cancer in an animal or human population. Many carcinogens have been identified in experimental animals, but because of dose-related effects and the metabolic differences among species, the relevance of these studies to humans is not always clear. It is important to stress that (1) the cause of most common human cancers is unknown; (2) most cases of cancer are probably multifactorial in origin; and (3) except for cigarette smoking, the agents discussed below have been implicated in only a small percentage of cases.
4. Chemical carcinogenesis
It has been over 200 years since the London surgeon Sir Percival Pott correctly attributed scrotal skin cancer in chimney sweeps to chronic exposure to soot. A few years later, based on this observation, the Danish Chimney Sweeps Guild ruled that its members must bathe daily. No public health measure since that time has achieved so much in the control of a form of cancer. Since that time, hundreds of chemicals have been shown to be carcinogenic in animals.
Main characteristic of chemicals carcinogens.
§ They are of extremely diverse structure and include natural and synthetic products.
§ Some are direct reacting and require no chemical transformation to induce carcinogenicity, but most are indirect reacting and become active only after metabolic conversion. Such agents are referred to as procarcinogens, and their active end products are called ultimate carcinogens.
§ All direct-reacting and ultimate chemical carcinogens are highly reactive electrophiles (i.e., have electron-deficient atoms) that react with the electron-rich atoms in RNA, cellular proteins, and, mainly, DNA.
§ The carcinogenicity of some chemicals is augmented by agents that by themselves have little, if any, transforming activity. Such augmenting agents traditionally have been called promoters; however, many carcinogens have no requirement for promoting agents.
§ Several chemical carcinogens may act in concert with other types of carcinogenic influences (e.g., viruses or radiation) to induce neoplasia.
Direct-acting agents, as already noted, require no metabolic conversion to become carcinogenic. They are in general weak carcinogens but are important because some of them are cancer chemotherapeutic drugs (e.g., alkylating agents) that have successfully cured, controlled, or delayed recurrence of certain types of cancer (e.g., leukemia, lymphoma). This situation is even more tragic when their initial use has been for non-neoplastic disorders, such as rheumatoid arthritis. The risk of induced cancer is low, but the fact that it exists dictates jodicious use of such agents.
The designation indirect-acting agent refers to chemicals that require metabolic conversion before they become active. Some of the most potent indirect chemical carcinogens-the polycyclic hydrocarbons-are present in fossil fuels. Polycyclic agents may be produced in the combustion of organic substances. For example, benzo[a]pyrene and other carcinogens are formed in the high-temperature combustion of tobacco in cigarette smoking. These products are implicated in the causation of lung cancer in cigarette smokers.
Polycyclic hydrocarbons also may be produced from animal fats during the process of broiling meats and are present in smoked meats and fish. The principal active products in many hydrocarbons are epoxides, which form covalent adducts (addition products) with molecules in the cell, principally DNA, but also with RNA and proteins.
Aflatoxin B1 is of interest because it is a naturally occurring agent produced by some strains of Aspergillus, a mold that grows on improperly stored grains and nuts. There is a strong correlation between the dietary level of this food contaminant and the incidence of hepatocellular carcinoma in some parts of Africa and the Far East.
Saccharin and cyclamates have been incriminated as carcinogens in experimental animals, but because induction of cancer with these artificial sweeteners requires extremely large doses, their role in human carcinogenesis remains in doubt. Finally, vinyl chloride, arsenic, nickel, chromium, insecticides, fungicides, and polychlorinated biphenyls (PCBs) are potential carcinogens in the workplace and about the house.
Because malignant transformation results from mutations that affect protooncogenes and cancer suppressor genes, it should come as no surprise that most chemical carcinogens are mutagenic. Although any gene may be the sasaran of chemical carcinogens, RAS gene mutations are particularly common in several chemically induced cancers in rodents. Among tumor suppressor genes, TP53 is an important target. Specific chemical carcinogens, such as aflatoxin B1, produce characteristic mutations in the TP53 gene. The association is sufficiently strong to incriminate aflatoxin, if the analysis of the TP53 gene reveals the signature mutation. These associations are proving useful tools in epidemiologic studies of chemical carcinogenesis.
It was mentioned earlier that carcinogenicity of some chemicals is augmented by subsequent administration of promoters (e.g., phorbol esters, hormones, phenols, and drugs) that by themselves are nontumorigenic. To be effective, repeated or sustained exposure to the promoter must follow the application of the mutagenic chemical, or initiator. The initiation-promotion sequence of chemical carcinogenesis raises an important question: Since promoters are not mutagenic, how do they contribute to tumorigenesis? Although the effects of tumor promoters are pleiotropic, induction of cell proliferation is a sine qua non of tumor promotion. Tetra-decanoylphorbol-acetate (TPA), a phorbol ester and the best-studied tumor promoter, is a powerful activator of protein kinase C, an enzyme that is a crucial component of several signal transduction pathways, including those activated by growth factors. TPA also causes growth factor secretion by some cells. It seems most likely that while the application of an initiator may cause the mutational activation of an oncogene such as RAS, subsequent application of promoters leads to clonal expansion of initiated (mutated) cells. Such cells (especially after RAS activation) have reduced growth factor requirements and may be less responsive to growth-inhibitory signals in their extracellular milieu. Forced to proliferate, the initiated clone of cells suffers additional mutations, developing eventually into a malignant tumor.
The concept that sustained cell proliferation increases the risk of mutagenesis, and hence neoplastic transformation, is also applicable to human carcinogenesis. The influence of estrogens on the occurrence of breast cancers may relate in part to the proliferative effects of estrogen on mammary ductal epithelium. The fact that many breast cancers express estrogen receptors and benefit from estrogen receptor antagonists supports a role for estrogen in breast cancer.
It must be emphasized that carcinogen-induced damage to DNA does not necessarily lead to initiation of cancer. Several forms of DNA damage (incurred spontaneously or through the action of carcinogens) can be repaired by cellular enzymes. Were this not the case, the incidence of environmentally induced cancer in all likelihood would be much higher.
In group of physical factors of tumorogenesis the most important and most often is radiation, whatever its source-UV rays of sunlight, x-rays, nuclear fission, radionuclides is an established carcinogen. The evidence is so voluminous that only a few examples are given. Many of the pioneers in the development of roentgen rays developed skin cancers. Miners of radioactive elements have suffered a ten-fold increased incidence of lung cancers. Follow-up of survivors of the atomic b0ms dropped on Hiroshima and Nagasaki disclosed a markedly increased incidence of leukemia-principally acute and chronic myelocytic leukemia-after an average latent period of about 7 years. Decades later, the leukemia risk for individuals heavily exposed is still above the level for control populations, as is the mortality rate from thyroid, breast, colon, and pulmonary carcinomas and others. The nuclear power accident at Chernobyl in the former Soviet Union continues to exact its toll in the form of high cancer incidence in the surrounding areas. Even therapeutic irradiation has been documented to be carcinogenic. Papillary thyroid cancers have developed in approximately 9% of individuals exposed during infancy and childhood to head and neck irradiation.
It is abundantly clear that radiation is strongly oncogenic. This effect of ionizing radiation is related to its mutagenic effects; it causes chromosome breakage, translocations, and, less frequently, point mutations. This effects may be due to activation of lipid peroxidation. Biologically, double-stranded DNA breaks seem to be the most important for radiation carcinogenesis. There also is some evidence that nonlethal doses of radiation may induce genomic instability, favoring carcinogenesis. Because the latent period of irradiation-associated cancers is extremely long, it seems that cancers emerge only after the progeny of initially damaged cells accumulate additional mutations, induced possibly by other environmental factors.
The oncogenic effect of UV rays merits special mention because it highlights the importance of DNA repair in carcinogenesis. Natural UV radiation derived from the sun can cause skin cancers (melanomas, squamous cell carcinomas, and basal cell carcinomas). At greatest risk are fair-skinned people who live in locales that receive a great deal of sunlight. Cancers of the exposed skin are particularly common in Australia and New Zealand. Nonmelanoma skin cancers are associated with total cumulative exposure to UV radiation, whereas melanomas are associated with intense intermittent exposure-as occurs with sunbathing. UV light has several biologic effects on cells. Of particular relevance to carcinogenesis is the ability to damage DNA by forming pyrimidine dimers. This type of DNA damage is repaired by a complex set of proteins that effect nucleotide excision repair. With extensive exposure to UV light, the repair systems may be overwhelmed, and skin cancer results. The importance of nucleotide excision repair is illustrated dramatically in an inherited disease called xeroderma pigmentosum. In these individuals, the nucleotide excision repair mechanism is defective or deficient, and there is a greatly increased predisposition to skin cancers. UV light characteristically causes mutations in the TP53 gene. Three other disorders of DNA repair and genomic instability-ataxia-telangiectasia, Fanconi anemia, and Bloom syndrome-also are characterized by an increased risk of cancer, related to some inability to repair environmentally induced DNA damage.
6. Biological oncogenesis
The study of oncogenic retroviruses in animals has provided spectacular insights into the genetic basis of cancer. Animal retroviruses transform cells by two mechanisms. Some, called acute transforming viruses, contain a transforming viral oncogene (v-onc), such as V-SRC, V-ABL, or V-MYB. Others, called slow transforming viruses (e.g., mouse mammary tumor virus), do not contain a v-onc, but the proviral DNA is always found inserted near a cellular oncogene. Under the influence of a strong retroviral promoter, the adjacent normal or mutated cellular oncogene is overexpressed. This mechanism of transformation is called insertional mutagenesis. With this brief summary of retroviral oncogenesis in animals, we can turn to the only known human retrovirus that is associated with cancer.
RNA oncogenic viruses
Human T-Cell Leukemia Virus Type 1. Human T-cell leukemia virus-1 (or human T-cell lymphotropic virus type 1 -HTLV-1) is associated with a form of T-cell leukemia/lymphoma that is endemic in certain parts of Japan and the Caribbean basin but is found sporadically elsewhere. HTLV-1 has tropism for CD41 T cells, and this subset of T cells is the major sasaran for neoplastic transformation. Leukemia develops in only about 1% of infected individuals after a long latent period of 20 to 30 years.
HTLV-1 does not contain a v-onc, and in contrast to slow transforming retroviruses, no consistent integration next to a cellular oncogene has been discovered, but in addition to the usual retroviral genes, a unique region called pX which encodes several proteins, including one called TAX. The TAX protein can activate the transcription of several host cell genes, including genes encoding the cytokine IL-2 and its receptor and the gene for GM-CSF and repress the function of tumor suppressor genes (TP53). The following scenario is emerging: HTLV-1 infection stimulates proliferation of T cells by the TAX gene, which turns on genes that encode IL-2 and its receptor, setting up an autocrine system for proliferation. Production of GM-CSF increased too. All this factors induce increased secretion of IL-1 (cell mitogen) and inhibition of growth-suppressive pathways. Initially the T-cell proliferation is polyclonal because the virus infects many cells. The proliferating T cells are at increased risk of secondary transforming events (mutations), which lead ultimately to the outgrowth of a monoclonal neoplastic T-cell population.
As with RNA viruses, several oncogenic DNA viruses that cause tumors in animals have been identified. Four DNA viruses-HPV (Human papillomavirus), Epstein-Barr virus (EBV) human herpesvirus 8 (HHV-8, also called Kaposi sarcoma herpesvirus), and HBV-are of special interest because they are strongly associated with human cancer.
Epidemiologic studies suggest that carcinoma of the cervix is caused by a secually transmitted agent, and HPV is strongly linked to this cancer. DNA sequences of HPV are found in 75% to 100% of invasive squamous cell cancers and their presumed precursors (i.e., severe dysplasias and carcinoma in situ).
Infection with high-risk HPV types simulates the loss of tumor suppressor genes, activates cyclins, inhibits apoptosis, and combats cellular senescence. Infection with HPV itself is not sufficient for carcinogenesis. For example, when human keratinocytes are transfected with DNA from HPV31 in vitro, they are immortalized, but they do not form tumors in experimental animals. Cotransfection with a mutated RAS gene results in full malignant transformation. These data strongly suggest that HPV in all likelihood acts in concert with other environmental factors.
EBV has been implicated in the pathogenesis of several human tumors: Burkitt lymphoma, post-transplant lymphoproliferative disease, primary central nervous system lymphoma in AIDS patients, nasopharyngeal carcinoma.
Burkitt lymphoma is endemic in certain parts of Africa and is sporadic elsewhere. EBV exhibits strong tropism for B cells and infects many B cells, causing them to proliferate, immortalization of B cells. These cell lines express several EBV-encoded antigens.
The molecular basis of B-cell proliferations induced by EBV is complex. One of the EBV-encoded genes acts as an oncogene, it promotes B-cell proliferation by activating signaling pathways via the B-cell surface molecule CD40, prevents apoptosis by activating BCL2.
In immunologically normal individuals, EBV is a cause of episode of infectious mononucleosis. In regions of the world where Burkitt lymphoma is endemic, concomitant (endemic) malaria (or other infections) impairs immune competence, allowing sustained B-cell proliferation. In addition, the B cells do not express cell surface antigens that can be recognized by host T cells. Relieved from immunoregulation, such B cells are at increased risk of acquiring mutations, such as the t(8;14) translocation, which activates the MYC oncogene and is a consistent feature of this tumor. The activation of MYC causes further loss of growth control, and the stage is set for additional gene damage, which ultimately leads to the emergence of a monoclonal neoplasm.
The epidemiologic evidence linking chronic HBV infection with hepatocellular carcinoma is strong, but the mode of action of the virus in tumor production is not fully elucidated. The HBV genome does not encode any transforming proteins, and there is no consistent pattern of integration in liver cells. HBV DNA is integrated, however, in 90% of patients with liver cancer who are positive for hepatitis surface B antigen, and the tumors are clonal with respect to these insertions. The oncogenic effect of HBV seems to be multifactorial. First, by causing chronic liver cell injury and accompanying regeneration, HBV predisposes the cells to mutations, caused possibly by environmental agents (e.g., dietary toxins). Second, an HBV-encoded regulatory element called HBx disrupts normal growth of infected liver cells by transcriptional activation of several growth-controlling genes. Third, cytosolic signal transduction pathways (e.g., RAS-MAP kinase) are turned on (recall TAX proteins of HTLV-1). Whether HBx also causes inactivation of TP53 is controversial. The role of the HBx gene in hepatic curcinogenesis is supported by the development of hepatocellular carcinomas in mice that are transgenic for this gene. Finally, in some patients, viral integration seems to cause secondary rearrangements of chromosomes, including multiple deletions that may harbor unknown tumor suppressor genes. Thus, it seems that virus-induced gene damage in regenerating liver cells may set the stage for multistep carcinogenesis.
Although not a DNA virus, hepatitis C virus (HCV) also is strongly linked to hepatocellular carcinoma. In general, the mechanism of HCV-related liver cancer is similar to that described for HBV. Extensive death of liver cells with their regeneration, and disruption of growth regulation are important factors. Unlike HBV, HCV does not contain the X-protein.
First incriminated as a cause of peptic ulcers, H. pylori now has acquired the dubious distinction of being blamed for causation of gastric carcinoma and gastric lymphoma. Their pathogenesis involves initial chronic gastritis that causes lymphoid follicles to develop in the gastric mucosa. It is thought that H. pylori infection leads to the formation of H. pylori-reactive T cells, which in turn cause polyclonal B-cell proliferations. In time, a monoclonal B-cell tumor emerges in the proliferating B cells, perhaps as a result of accumulation of mutations in growth-regulatory genes. In keeping with this, early in the course of disease, eradication of H. pylori "cures" the lymphoma by removing antigenic stimulus for T cells.
In addition to B-cell lymphomas, H. pylori has now been linked strongly to the pathogenesis of gastric epithelial cancers. Here the scenario seems to be an initial development of chronic gastritis, followed by gastric atrophy, intestinal metaplasia of the lining cells, dysplasia, and cancer. This sequence takes decades to complete and occurs in only 3% of infected patients.
Although H. pylori causes three diseases (peptic ulcer, gastric lymphoma, and gastric carcinoma), these conditions do not occur often in the same patient. For unknown reasons, patients who have duodenal ulcers (not gastric ulcers) almost never develop gastric carcinoma.
7. Malignent cells features
Malignant cells have grate number of special characteristics, gived them ability to live in different condition. Some of them will discus here.
Structural Differences
Lack of differentiation means that the special features of the normal cell are imperfectly expressed: a ciliated cell will have fewer cilia, a secretory cell less secretion, and so on. This fact has given rise to the common and synonymous terms anaplasia, and dedifferentiation, both implying that the cancer cell has somehow regressed to a lesser state of differentiation. However, it seems unlikely that tumors consist of mature cells that regress. The current concept of carcinogenesis is that tumors contain undifferentiated stem cells whose progeny fail to mature. In other words, the tumor cell is born in a state of low differentiation and does not become immature by dedifferentiating itself.
Some kind of backward differentiation does indeed occur in malignant tumors as they change from bad to worse, a phenomenon known (backwardly) as tumor progression.
Fast growth. Features of fast-growing cells are easy to grasp:
· Cytoplasmic basophilia is increased, which means more RNA and thus more active protein synthesis. The electron microscope shows many free ribosomes, which correspond to the fact that the cell is busy making more of itself rather than producing proteins for export.
· Nucleoli increase in size and number (remember that RNA is synthesized within them), and the nucleolar organizer region may be abnormal.
· Glycogen content is high, as it is in embryonic cells. This abundance of glycogen correlates with the anaerobic glycolysis typical of embryonic as well as of tumor cells.
Atypical features. The features of atypia are especially important because atypia tends to parallel the degree of aggressiveness. It can hit virtually every aspect of cellular structure. For example:
· Size and shape of the cell are abnormal. Malignancy is linked to cytoskeletal disturbances, which lead to internal disarray as well as to mechanical effects on cell shape.
· The shape of the nucleus is irregular. This is one of the most reliable criteria of malignancy, especially when the size and shape of the nucleus vary from cell to cell: most of the asing nuclei contained asing chromosomes, ring-shaped, dicentric, or with other defects. Thus, abnormalities in nuclear shape can be considered primarily as signs of genetic instability.
· Mitoses are too numerous and some may be abnormal. Multiple centrosomes are often associated with the lack of a powerful tumor suppressor gene, p53; the lack of this controlling gene could allow centrosomes to replicate when they should not. By increasing the frequency of mitotic errors, the centrosomes could also confer a mutator phenotype to tumors.
· Cell-specific organelles are distorted or lost.
· Secretion becomes irregular, as best seen in mucussecreting cells.
Behavior in Culture
Immortality. Transformed cells can grow forever. A sadly famous lady named Henrietta Lacks died in 1951 of a cervical carcinoma; cells from her tumor, the ubiquitous HeLa cells, are still growing relentlessly in laboratories throughout the world. Note that this immortality does not compare with the immortality of bacteria: in real life, every strain of immortal malignant cells dies when it kills its host unless it is cultured like the HeLa cells. Every case of cancer is therefore a new disease. Telomere-telomerase mechanism: linear chromosomes must be capped by telomeres, which are progressively eroded (a lethal pathway for the cell) unless they are rebuilt by the enzyme telomerase. Virtually all tumors express telomerase, but telomerase expression by itself does not imply transformation, witness the telomerase-positive stem cells. Expression of the human telomere gene is regulated by the immortalizing oncoprotein Myc, which is up-regulated in most human cancers.
Loss of anchorage dependence. As mentioned earlier, normal cells prefer to grow on a surface; they become attached to it, spread out, and begin to replicate. In contrast, transformed cells can also do well in a fluid medium such as soft agar, in which they maintain a more rounded shape. Cytoskeletal changes are probably involved.
Loss of contact inhibition. Transformed cells grow to cover all available space, then continue to grow and pile up over each other haphazardly. Normal cells usually stop when they contact each other, at which point they constitute a confluent sheet with little or no cell overlap. The term contact inhibition has been used in various ways; for some it has meant inhibition of movement and for others inhibition of growth, hence the current tendency to replace the phrase loss of contact inhibition with the cumbersome decreased density-dependent inhibition of growth.
Loss of orientation on an oriented substrate. Malignant cells growing on a surface with a distinctive pattern have partially lost the ability to align themselves accordingly. This is, we presume, another consequence of a faulty cytoskeleton.
Decreased requirement for growth factors. Normal cells tend to be fussy about the medium in which they are nurtured; special mixtures of growth factors must be worked out for each type. Transformed cells are much easier to grow and require less serum (i.e., fewer growth factors). The reason is now apparent: malignant cells supply their own growth factors by a curious property known as autocrine secretion.
Functional and Biochemical Changes
Motility and chemotaxis. Many types of cancer cells can move around rather like amoebae, although their normal counterparts may be stationary. This characteristic helps us understand the mechanism of invasiveness; it was actually shown in vitro that the fastest moving cells are the most invasive. Moreover, some cancer cells secrete a factor that accelerates their motion and even directs it by chemotaxis.
Surface-related changes
· Decreased adhesion between cells. In a classic experiment D. R. Coman of Philadelphia showed in 1944 that cells of a carcinoma are more easily pulled apart than their normal counterparts. Malignant cells in general have fewer intercellular contacts and fewer attachments to the stroma because action-to-membrane attachments are one of the prime targets of transformation-related disturbances.
· Altered intercellular communication. Overall, it seems that decreased communication between cells favors cell proliferation: for example, mice lacking connexin32 (a gap junction protein of liver cells) spontaneously developed 8 times more liver tumors than control mice.
· communicating junctions also exist between the neoplastic cells of a given tumor.
· oncogene regulates intercellular communication and growth.
· Tendency to shed surface molecules, including proteins, glycoproteins, and enzymes (collagenase can help the malignant cell work its way through the extracellular matrix, fibronectin may lead to exaggerated clotting). Some of the shed molecules can be found in the blood and are therefore available as tumor markers, a useful device for diagnosing the presence of a particular type of tumor or for monitoring its response to therapy.
Cancers are far more threatening to the host than benign tumors are. Nonetheless, both types of neoplasia may cause problems because of location and impingement on adjacent structures, effects on functional activity such as hormone synthesis, and production of bleeding and secondary infections when the lesion ulcerates through adjacent natural surfaces. Cancers also may be responsible for cachexia (wasting) or paraneoplastic syndromes.
Location and size are crucial in benign and malignant tumors. A small (1-cm) pituitary adenoma can compress and destroy the surrounding normal gland and give rise to hypopituitarism. A 0.5-cm leiomyoma in the wall of the renal artery may lead to renal ischemia and serious hypertension.
Hormone production is seen with benign and malignant neoplasms arising in endocrine glands. Adenomas and carcinomas arising in the β cells of the islets of the pancreas often produce hyperinsulinism, sometimes fatal. Analogously, some adenomas and carcinomas of the adrenal cortex elaborate corticosteroids that affect the patient (e.g., aldosterone, which induces sodium retention, hypertension, and hypokalemia).
Ulceration through a surface with consequent bleeding or secondary infection needs no further comment.
Cancer cachexia. Many cancer patients suffer progressive loss of body fat and lean body mass, accompanied by profound weakness, anorexia, and anemia. This wasting syndrome is referred to as cachexia. Usually an intercurrent infection brings an end to the slow deterioration. There is in general some correlation between the size and extent of spread of the cancer and the severity of the cachexia. Small, localized cancers are generally silent and produce no cachexia, but there are many exceptions.
The origins of cancer cachexia are multifactorial. Anorexia is a common dilema in patients who have cancer, even those who do not have tumors of the gastrointestinal tract. Reduced food intake has been related to abnormalities in taste and in the central control of appetite, but reduced calorie intake is not sufficient to explain the cachexia of malignancy. In patients with cancer, calorie expenditure remains high, and basal metabolic rate is increased, despite reduced food intake. This is in contrast to the lower metabolic rate that occurs as an adaptational response in starvation. The basis of these metabolic abnormalities is not fully understood. Perhaps circulating factors such as TNF and IL-1, released from activated macrophages, are involved. TNF suppresses appetite and inhibits the action of lipoprotein lipase, inhibiting the release of free fatty acids from lipoproteins. A protein-mobilizing factor that causes breakdown of skeletal muscle proteins by the ubiquitin-proteosome pathway has been detected in the serum of cancer patients. In healthy animals, injection of this material causes acute weight loss without causing anorexia. Other molecules with lipolytic action also have been found. There is no satisfactory treatment for cancer cachexia other than removal of the underlying cause, the tumor.
Paraneoplastic syndromes. Symptom complexes other than cachexia that occur in patients with cancer and that cannot be readily explained by local or distant spread of the tumor or by the elaboration of hormones indigenous to the tissue of origin of the tumor are referred to as paraneoplastic syndromes. They appear in 10% to 15% of patients with cancer, and it is important to recognize them for several reasons:
· They may represent the earliest manifestation of an occult neoplasm.
· In affected patients, they may represent significant clinical problems and may be lethal.
· They may mimic metastatic disease and confound treatment.
The paraneoplastic syndromes are diverse and are associated with many different tumors. The most common syndromes are hypercalcemia, Cushing syndrome, and hypercoagulability. Cushing syndrome as a paraneoplastic phenomenon is usually related to ectopic production by the cancer of ACTH or ACTH-like polypeptides. The mediation of hypercalcemia, another common paraneoplastic syndrome, is multifactorial. Perhaps the most important factor is the synthesis of a parathyroid hormone-related protein (PTHrP) by tumor cells (squamous cell carcinomas of the lung). Although structurally PTHrP resembles parathyroid hormone, it can be distinguished from it by specific assays. Also implicated are other tumor-derived factors, such as TGF-α, a polypeptide factor that activates osteoclasts, and the active form of vitamin D. Another possible mechanism for hypercalcemia is widespread osteolytic metastatic disease of bone, but it should be noted that hypercalcemia resulting from skeletal metastases is not a paraneoplastic syndrome. Paraneoplastic syndromes may take many other forms, such as hypercoagulability leading to venous thrombosis and nonbacterial thrombotic endocarditis or the development of clubbing of the fingers and hypertrophic osteoarthropathy in patients with lung carcinomas. Still others are discussed in the consideration of cancers of the various organs of the body
Sometimes one tumor induces several syndromes concurrently. For example, bronchogenic carcinomas may elaborate products identical to or having the effects of ACTH, antidiuretic hormone, parathyroid hormone, serotonin, human chorionic gonadotropin, and other bioactive substances.
Malignant transformation, as has been discussed, is associated with complex genetic alterations, some of which may result in the expression of proteins that are seen as non-self by the immune system. The idea that tumors are not entirely self was conceived by Ehrlich, who proposed that immune-mediated recognition of autologous tumor cells may be a "positive mechanism" capable of eliminating transformed cells. Subsequently, Lewis Thomas and McFarlane Burnet formalized this concept by coining the term immune surveillance to refer to recognition and destruction of non-self tumor cells on their appearance. The fact that cancers occur suggests that immune surveillance is imperfect; however, the fact that some tumors escape such policing does not preclude the possibility that others may have been aborted. It is necessary to explore certain questions about tumor immunity: What is the nature of tumor antigens? What host effector systems may recognize tumor cells? Is tumor immunity effective against spontaneous neoplasms
Antigens that elicit an immune response have been shown in many experimentally induced tumors and in human cancers. They can be classified broadly into two categories: tumor-specific antigens, which are present only on tumor cells and not on any normal cells, and tumor-associated antigens, which are present on tumor cells and on some normal cells. Experimental studies and the study of tumor-infiltrating lymphocytes in humans have revealed an important role for CD8+ cytotoxic T cells (CTLs) in tumor immunity. As is well known, CTLs recognize peptide antigens presented on the cell surface by major histocompatibility complex (MHC) class I molecules.
Cancer-Testis Antigens. These antigens are encoded by genes that are silent in all 4dukt tissues except the t3st1s-hence their name. Although the protein is present in the t3st1s, it is not expressed on the cell surface because sperms do not express MHC I antigens. Thus, for all practical purposes, these antigens are tumor specific.
Tissue-Specific Antigens. Antigens in this category are best considered differentiation-specific antigens, and they are expressed on tumor cells and their untransformed counterparts. Such antigens include melanocyte-specific proteins which are expressed on normal melanocytes and melanomas. Thus, cytotoxic T cells directed against these antigens would destroy not only melanoma cells but also normal melanin-containing cells.
Antigens Resulting From Mutational Change in Proteins. Antigens in this category are derived from mutant oncoproteins and cancer suppressor proteins. Unique tumor antigens arise from products of RAS, TP53, and CDK4 genes, which frequently are mutated in tumors. Because the mutant proteins are present only in tumors, their peptides are expressed only in tumor cells.
Overexpressed Antigens. These tumor antigens are products of normal genes that are overexpressed because of gene amplification or other mechanisms. To this category belongs the HER-2 (neu) protein, which is overexpressed in 30% of breast and ovarian cancers. Although present in normal ovarian and breast cells, its level is generally too low for T-cell recognition.
Viral Antigens. Antigens derived from oncogenic viruses such as HPV and EBV can be targeted by CD8+ T cells. Such tumor antigens are shared between all tumors of similar type in different patients. They can be effective targets for immunotherapy because they are not expressed in normal cells.
Other Tumor Antigens. Mucins can give rise to tumor-specific antigens. In some cancers, such as those derived from pancreas, ovary, and breast, underglycosylation of mucins generates epitopes that previously were masked by carbohydrates. Therefore, these antigens, for all practical purposes, are tumor specific.
Oncofetal Antigens. Oncofetal antigens or embryonic antigens, such as carcinoembryonic antigen (CEA) and α-fetoprotein, are expressed during embryogenesis but not in normal 4dukt tissues. Antibodies can be raised against these, and they are useful for detection of oncofetal antigens. These antigens serve as serum markers for cancer.
Differentiation-Specific Antigens. Differentiation-specific antigens, such as CD10 and prostate-specific antigen (PSA), are expressed on neoplastic and normal B cells and on benign and malignant prostatic epithelium, respectively. These serve mainly as diagnostic markers for the type of cell involved in transformation.
All this antigens may be used for early diagnostics of neoplasm.
Cell-mediated and humoral antitumor immunity
Cytotoxic T lymphocytes. The role of specifically sensitized cytotoxic T cells in experimentally induced tumors is well established. In humans, they seem to play a protective role, chiefly against virus-associated neoplasms. The presence of MHC-restricted CD8+ cells that can kill autologous tumor cells within human tumors suggests that the role of T cells in immunity against human tumors may be broader than previously suspected. They recognize antigens described earlier. In some cases, such CD8+ T cells do not develop spontaneously in vivo but can be generated by immunization with tumor antigen-pulsed dendritic cells.
Natural killer cells (NK) cells are lymphocytes that are capable of destroying tumor cells without prior sensitization; they may provide the first line of defense against tumor cells. After activation with IL-2, NK cells can lyse a wide range of human tumors, including many that seem to be nonimmunogenic for T cells. T cells and NK cells seem to provide complementary antitumor mechanisms. Tumors that fail to express MHC class I antigens cannot be recognized by T cells, but these tumors may trigger NK cells because the latter are inhibited by recognition of normal autologous class I molecules. The triggering receptors on NK cells are extremely diverse and belong to several gene families. They recognize stress-induced antigens that are expressed mainly on tumor cells. In addition to direct lysis of tumor cells, NK cells can also participate in antibody-dependent cellular cytotoxicity.
Activated macrophages exhibit selective cytotoxicity against tumor cells in vitro. T cells, NK cells, and macrophages may collaborate in antitumor reactivity because interferon-γ, a cytokine secreted by T cells and NK cells, is a potent activator of macrophages. These cells may kill tumors by mechanisms similar to those used to kill microbes (e.g., production of reactive oxygen metabolites; or by secretion of tumor necrosis factor (TNF). In addition to its many other effects, this cytokine is lytic for several tumor cells.
Humoral mechanisms. These may participate in tumor cell destruction by two mechanisms: (1) activation of complement and (2) induction of antibody-dependent cellular cytotoxicity by NK cells
Most cancers occur in individuals who do not suffer from any overt immunodeficiency. If immunosurveillance exists, how do cancers evade the immune system in immunocompetent hosts? Several escape mechanisms have been proposed:
Selective outgrowth of antigen-negative variants. During tumor progression, strongly immunogenic subclones may be eliminated.
Loss or reduced expression of histocompatibility antigens. Tumor cells may fail to express normal levels of human leukocyte antigen (HLA) class I, escaping attack by cytotoxic T cells. Such cells, however, may trigger NK cells.
Lack of costimulation. Sensitization of T cells requires two signals, one by foreign peptide presented by MHC and the other by costimulatory molecules; although tumor cells may express peptide antigens with class I molecules, they often do not express costimulatory molecules. This not only prevents sensitization but also may render T cells anergic or cause them to undergo apoptosis.
Immunosuppression. Many oncogenic agents (e.g., chemicals and ionizing radiation) suppress host immune responses. Tumors or tumor products also may be immunosuppressive. For example, transforming growth factor (TGF)-β, secreted in large quantities by many tumors, is a potent immunosuppressant. In some cases, the immune response induced by the tumor (e.g., activation of regulatory T cells) may inhibit tumor immunity. Another clever mechanism used by tumors is to express Fas ligand, which engages Fas on the surface of T cells and sends a death signal to the immune cells.
Also, we can find increased frequency of cancers in immunodeficient hosts. About 5% of individuals with congenital immunodeficiencies develop cancers, a rate that is about 200 times that for individuals without such immunodeficiencies. Analogously, immunosuppressed transplant recipients and patients with AIDS have increased numbers of malignancies.
10. The theory of tumor iniciation, promotion and progression
The concept that tumors develop by steps was born in the 1930s. Working on rabbit tumors produced by a virus or tar, Rous and his co-workers noticed that the path to malignancy was not a continuous slope. At first they obtained hyperplastic lesions that behaved as benign warts or papillomas; but then these papillomas did not become globally more and more atypical until they could be called cancers. Instead, most cancers arose quite suddenly and only in a part of a papilloma, as a wholly new and different event.
Intensive work on the multistep theory soon produced a dogma: tumor production occurs in two main phases, initiation and promotion, followed by a relentless, stepwise increase in malignancy called progression.
Initiation and Promotion
Initiation (or transformation) is characterized by the ability to transform healthy cells into cells with endless growth. Such ability can be the result of mutation or genome changes as a consequence of disregulatory processes. It is conceived as a quick, almost instantaneous process; if it is repeated, the effect on the tissue is additive. Initiators can be chemical, physical, or biological. They do not cause cell proliferation. Initiated cells are morphologically indistinguishable from normal cells, at least to the present.
Promotion is the second stage in the mechanism of carcinogenesis. The transformed cells may remain in the tissue in inactive form for a long time. Additional influence of cocarcinogenic factor stimulates cell reproduction and formation of tumor node. Promotion is viewed as a slow process; its effect is reversible and nonadditive. Many promoters cause cells to multiply; in fact, there is some consensus that hyperplasia is a typical effect of promoters. Some promoters have a certain degree of organ specificity
A puzzling fact had been reported off and on since the 1920s: if the skin of an experimental animal is painted with tar and then biopsied for microscopic study, tumors often arise at the site of the biopsy. The basic plan was to tar rabbit ears throughout a period somewhat less than is ordinarily required to elicit growths, and then to wound the ear. The results were clear; wounding was enough to encourage latent neoplastic cells. The tar had somehow initiated the neoplastic process, and the wound promoted it.
The principle of initiation by a subcarcinogenic dose was retained, but wounding as a promoter was replaced with a local irritant; the choice was croton oil. This technique of promotion became more scientific when two laboratories, one in Germany, the other in New York, independently isolated the irritating principle of croton oil and named it, respectively, phorbol myristate acetate (PMA) and tetradecanoyl phorbol acetate (TPA) the latter name seems to have won. Many other initiators and promoters were proposed, but the most popular of the promoters remains TPA
Eventually the basic rules of the initiation-promotion routine were worked out. To begin, promotion before initiation produces no tumors.
However, the theory of initiation and promotion has its flaws, as all theories do. It was derived largely from experiments based on painting mouse skin, a somewhat limited sample of carcinogenesis. Most carcinogens are initiators as well as promoters, a fact that is brushed off by deciding that these are complete carcinogens. Furthermore, some promoters can also produce tumors. Last, the initiation - promotion scheme requires a mutagen, whereas it is now well known that many cancers arise without mutagens. In essence, then, the facts appear to tell us that the initiation-promotion theory offers a satisfactory paradigm for interpreting some, and perhaps most cancers of the skin and other sites, but not all cancers.
Tumor progression
Progression is realized as stable qualitative changes of turner properties towards malignization.
Once malignant tumors have started to grow, they tend to go from bad to worse: this is how Rous and Kidd described in 1941 what is now called tumor progression, the third phase in the initiation-promotion-progression paradigm. The term implies a drive toward increasing malignancy of the tumor itself and of its metastases. The basic mechanism is thought to be a genetic instability of neoplastic cells. Progression is now understood more broadly as the effect of disturbances that may occur anywhere from chromosome to gene to DNA structure.
The role of clones in progression. After a single cell is transformed, new clones continue to appear; under constant evolutionary pressures, some cells are eliminated because of a biological disadvantage, others succeed because they are progressively less demanding of growth factors, less sensitive to drugs and X-rays, more invasive, more metastatic. The simpulan result is a polyclonal tumor.
These changes arise under the influence of several factors:
1. Not one but several cells become involved into primary carcinogenic that promotes formation of law sublines of cells in the growing tumor. A constant selection of the most viable cells goes on in the growing tumor under the influence of the changing conditions of its growth (nutrition, blood supply and innervation).
2. Change of genotype and phenotype of the cells resulting in progression may be connected with continuation of the effect of carcinogenic factors on the genome of tumor cells.
3. Acquisition of new properties by tumor cells, which is connected with superinfection by tumor and non-tumor viruses.
11. Metastases
A metastasis is a secondary tumor that grows separately from the primary and has arisen from detached, transported cells. In essence, it is a colony of the primary tumor. The seed that starts a metastatic growth can be transported by the blood or lymph, or by fluid in tissue spaces. Metastases represent the most lethal expression of malignancy and the most important concern of the treating physician. By the time the diagnosis of cancer is made, over half of the patients already have microscopic metastases and will die of them, because there is, overall, little hope for cure at that stage.
Lymphatogenous Metastasis
Malignant cells are carried by the lymphatics to the regional lymph nodes. The belief that cancerous cells spread first to the regional lymph nodes—where their advance may be temporarily arrested by the immune response—is the rationale for radical surgery, which removes both the primary neoplasm and the regional lymph nodes to thereby eliminate the most likely sites of early metastases. Removal of lymph nodes is performed only for those neoplasms in which lymphatic metastasis is common, eg, carcinoma and melanoma.
Hematogenous Metastasis
Entry of cancerous cells into the bloodstream is believed to occur during the early clinical course of many malignant neoplasms. Most of these malignant cells are thought to be destroyed by the immune system, but some become coated with fibrin and entrapped in capillaries. Skeletal metastases are common in cancer of the prostate, thyroid, lung, breast, and kidney. Adrenal metastases are common in lung cancer.
Entry of malignant cells into body cavities (eg, pleura, peritoneum, or pericardium) or the subarachnoid space may be followed by dissemination of the cells anywhere within these cavities; the rectovesical pouch and ovary are common locations for peritoneal metastasis in patients with gastric cancer. Cytologic examination of the fluid from these body cavities for the presence of malignant cells is an excellent method of confirming the diagnosis of metastasis.
Cancerous cells that spread to distant sites may remain dormant there (or at least remain slowly growing and undetectable), sometimes for many years. The presence of such dormant cancerous cells (or slowly growing subclinical metastases) has led to attempts to eradicate them by means of systemic chemotherapy after treatment of the primary tumor. While results have been encouraging in some types of disseminated cancer, including malignant lymphoma, choriocarcinoma, and testicular germ cell tumors, the overall cure rate is so low—and the morbidity of chemotherapy so high—as to question the validity of this approach for most malignant tumors.
Development of delayed metastases makes it difficult to pronounce a patient cured with any confidence. Survival for 5 years after treatment is considered a sign of cure for most cancers. However, 10- and 20-year survival rates are almost always lower than the 5-year survival rates, which suggests that many patients experience late metastases
The metastatic cascade
From the point of view of the malignant cell, invasion and metastasis require the ability to overcome a series of obstacles, which have been aptly compared to a decathlon, named the metastatic cascade. To produce a hematogenous metastasis a cell must separate itself from the tumor mass and move in the right direction; it must digest its way through the intercellular matrix, and then through a vascular basement membrane to penetrate the lumen of a vessel; once there, it must escape the various defensive systems of the blood, including antibodies, complement, macrophages, killer cells of various sorts, oxygen, and even blood clotting; when it reaches a vessel small enough to be embolized, it must survive the impact and the mechanical squeeze; then it must proceed in revetse, penetrate the endothclium and the basement membrane, escape a new set of dangerous cells (macrophages, lymphocytes), multiply, induce angiogenesis, and finally establish a tumor. In view of all these difficulties, it is not surprising that many tumor cells fail. At each step of the metastatic cascade the metastatic cells are selected by a basic principle: survival of the fittest, which contributes to the phenomenon of tumor progression.
A human gene, KiSS-1, encodes a peptide (metastin) that reduces the number of pulmonary metastases of a melanoma in the mouse. Most interestingly, metastin is abundant in the human placenta.
Data are available for all the steps of the metastatic cascade.
(1) Detachment
There is no question that malignant cells become detached from the tumor mass because they can be found in the bloodstream, single or in clusters.
Complete detachment from their neighbors may be due to
1. proteolytic enzymes diffusing outward from the necrotic core of the tumor.
2. their adhesion molecules are not properly expressed.
3. Active motility of tumor cells could also favor the detachment process, and there is ample proof that many types of malignant cells do show ameboid motion.
(2) Invasion
The interface between tumor and host is currently visualized as a zone of intense enzymatic activity: a grup band of matrix soaked in enzymes and their products, as well as growth factors and other cytokines. The malignant cells must digest their way through this gelatinous layer, using heparanase and collagenase specific for collagen fibrils and for basement membranes; they do so in part by appropriating stromal enzymes and using them mounted on their own surface. The enzymes critical for tumor invasion are metalloproteases. Mixed with these enzymes are their products, which can affect many different processes and thereby greatly complicate the issue. Growth pressure might be exploited by cancer cells forcing their way into the surroundings, but it cannot be the only mechanism. Active motility of cancer cells is well proven. It was calculated as far back as 1916 that the speed of cells observed in vitro would enable malignant cells to crawl from the breast to the axillary lymph nodes in 4 weeks.
(3) Penetration into the Blood Vessels
It should be basic three-step mechanism: attachment, lysis, and invasion. When tumor cells reach the perivascular basement membrane, they attach to it by means of laminin receptors (laminin is an adhesive molecule that reinforces basement membranes); then the tumor cells secrete collagenase (type 4), specific for the collagen of the basement membrane, and eventually move through. Tumor cells may not always need this arsenal: vessels in tumors are often defective and may lack basement membrane or the invading cell may punch its way through an endothelial cell, creating a temporary migration pore.
(4) Transport in the Bloodstream
Tumor cells are found in the blood of experimental animals as well as in humans. In humans it has been found repeatedly that trauma, including surgery, sends showers of tumor cells into the bloodstream. The number rarely exceeds 1000 per milliliter. There is no correlation between circulating cancer cells and number of metastases. Hazards encountered by tumor cells in the blood are many: coating with antibodies followed by lysis with complement, encounters with killer cells of various kinds and, according to recent studies, exposure to a toxic concentration of oxygen. The only possible advantage for the tumor cell might be the coating with platelets, which in some experimental systems seems to help the metastatic process. And then, within seconds of gaining entry into the bloodstream, tumor cells face the stress berat of embolization, which can be their demise.
(5) Embolization Followed by Cell Death
Most tumor cells injected intravenously are killed by biomechanical stress berat in minutes. The mechanical impact of embolism is fatal to many tumor cells because they are larger and less deformable than leukocytes. Biomechanical stress berat must be especially severe in the heart where capillaries receive a hefty squeeze at every beat, i.e., more than once per second. Similar effects apply to skeletal muscle.
(6) Embolization Followed by Growth
The embolic episode has been recorded cinematographically in vivo, quite a technical feat. It was shown that some tumor cells survive embolic stress berat and continue to circulate.
The malignant cell or cluster settles in a capillary or precapillary vessel where it is always tightly apposed to the endothelial surface; it is often associated with platelets (which may act as a supply of growth factors) and with some strands of fibrin. Within a few hours the malignant cell (be it isolated or part of a cluster) sends a pseudopod between the endothelial cells or through them and makes contact with the basement membrane, while flow may resume. Thereafter the cell may exit from the vessel and pursue its career outside or divide and grow into a metastatic lump that occludes the lumen. The diapedesis of a tumor cell appears surprisingly similar to that of a leukocyte. New vessels may begin to sprout toward the metastasis after 24 hours, and a tumor vascular network is visible at 4 days. The production of tumor angiogenesis factor (TAF) by the cancerous cells stimulates growth of new capillaries in the vicinity of tumor cells and encourages vascularization of the growing metastasis. The site of metastasis is most commonly the first capillary bed encountered by blood draining the primary site. Some types of cancer apparently favor particular metastatic sites, although the mechanisms responsible are unknown.
The purpose of accurate diagnosis of the specific tumor type is to enable the clinician to select an appropriate mode of therapy. Even with the best treatment, survival rates vary greatly for different types of neoplasms.
Surgery is the most effective variant of neoplasia treatment. For benign neoplasms surgical removal is curative. In a few cases, surgical removal may be difficult because of the location, eg, choroid plexus papillomas in the third ventricle. Surgical treatment of malignant neoplasms is more difficult because they tend to infiltrate tissues. Local excision requires careful pathologic examination (including frozen sections as required) of the margins of resection to ensure complete removal. For low-grade malignant neoplasms, wide local excision is frequently sufficient for cure. Incomplete removal leads to local recurrence. Malignant neoplasms with a high risk of early lymphatic metastasis are often treated by removal not only of the affected tissue but also of the lymph node group of primary drainage (radical surgery); in radical mastectomy, the axillary lymph nodes are dissected and removed with the breast.
Surgery alone is of little value when widespread metastases are present. However, surgical removal of isolated metastases may reduce tumor bulk, thereby enhancing the effects of chemotherapy and any residual immune response.
Many malignant neoplasms are sensitive to radiation. In general, the more rapidly growing the neoplasm, the more likely it is to be radiosensitive; however, sensitivity is not synonymous with cure. The effect of radiation in a given neoplasm can be predicted on the basis of past experience with radiation therapy in similar neoplasms.
Advances in cancer chemotherapy have greatly improved the outlook for many patients with cancer. Chemotherapy is the treatment of choice for many neoplasms such as malignant lymphoma and leukemia. Anticancer drugs act in one of several ways: (1) by interfering with cell metabolism and ribonucleic acid (RNA) or protein synthesis (antimetabolites); (2) by blocking deoxyribonucleic acid (DNA) replication and mitotic division (antimitotic agents); or (3) by exerting hormonal effects, eg, estrogens in prostate carcinoma and antiestrogenic agents such as tamoxifen in breast carcinoma.
Attempts to stimulate the immune system with adjuvants such as bacille calmette-guérin [vaccine] (BCG) have met with limited success. More specific immunotherapy using monoclonal antibodies developed against tumor-associated antigens has been used in the treatment of malignant melanoma, lymphoma, and some carcinomas. One promising approach uses the antibody to carry cytotoxic drugs, toxins, or radioisotopes to the tumor site
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