Tumor Immunology



Tumor Immunology



Learning Objectives


At the conclusion of this chapter, the reader should be able to:


• Compare the characteristics of benign and malignant tumors.


• Describe the epidemiology of cancer in adults and children.


• Explain the characteristics of the three major causative factors in human cancer.


• Compare the stages of carcinogenesis.


• Describe the aspects of cancer-related genes.


• Define and give examples of proto-oncogenes.


• Describe the role of oncogenes.


• Describe the characteristics of the major body defenses against cancer.


• Identify and discuss the characteristics of tumor markers.


• Discuss what’s new in cancer diagnostic testing.


• Compare various modalities for treating cancer.


• Analyze representative case studies.


• Correctly answer case study related multiple choice questions.


• Be prepared to participate in a discussion of critical thinking questions.


• Describe the principle and clinical applications of the prostate-specific antigen procedure.


• Correctly answer end of chapter review questions.



Key Terms



Oncology is that branch of medicine devoted to the study and treatment of tumors. The term tumor is commonly used to describe a proliferation of cells that produces a mass rather than a reaction or inflammatory condition. Tumors are neoplasms and are described as benign or malignant. Most tumors are of epithelial origin (ectoderm, endoderm, or mesoderm); the remaining tumors are of connective tissue origin (Fig. 33-1). The key distinction between benign and malignant tumors is the ability of malignant tumors to invade normal tissue and metastasize to other secondary sites.


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Figure 33-1 Embryonic primary germ layers. (Adapted from Larsen WJ: Human embryology, ed 3, Philadelphia, 2001, Churchill Livingstone.)


Cancer Stem Cells


Biology research studies have discovered that stem cells are critical for the generation of complex multicellular organisms and the development of tumors. To cure a cancer through stable long-term remission, the stem cell compartment of a tumor needs to be eradicated. Stem cells have three distinctive properties:



If normal self-renewal is subverted, it becomes abnormal self-renewal. If increased self-renewal occurs, combined with the intrinsic growth potential of stem cells, it may yield a malignant phenotype. It is possible that cancer stem cells can arise by mutation from normal stem cells or mutated progenitor cells (Fig. 33-2).


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Figure 33-2 For tumors in which cancer stem cells play a role, at least three scenarios are possible.
A, Mutation of a normal stem cell or progenitor cell may create a cancer stem cell, which will then generate a primary tumor (Panel A). B, During treatment with chemotherapy, most cells in a primary tumor may be destroyed, but if the cancer stem cells are not eradicated, the tumor may regrow and cause a relapse (Panel B). C, Cancer stem cells arising from a primary tumor may emigrate to distal sites and create metastatic lesions (Panel C). (From Jordan CT, Guzman ML, Noble M: Cancer stem cells, N Engl J Med 355:1253–1260, 2006.)


Types of Tumors


Benign Tumors


Benign tumors are often named by adding the suffix -oma to the cell type (e.g., lipoma), but there are exceptions (e.g., lymphomas, melanomas, hepatomas). Benign tumors arising from glands are called adenomas; those from epithelial surfaces are termed polyps or papillomas.


Benign tumors are characterized by the following:



Other types of tumors include non-neoplastic lesions associated with an overgrowth of tissue that is normally present in the organ (e.g., hyperplastic tissue) and choristomas, normal tissue in a foreign location (e.g., pancreatic tissue in the stomach).



Malignant Tumors


A malignant neoplasm of epithelial origin is referred to as carcinoma, or cancer. Those arising from squamous epithelium (e.g., esophagus, lung) are called squamous cell carcinomas, those arising from glandular epithelium (e.g., stomach, colon, pancreas) are called adenocarcinomas, and those arising from transitional epithelium in the urinary system are called transitional cell carcinomas.


Other types of malignant tumors include amine precursor uptake and decarboxylational tumors. These are neuroendocrine tumors that commonly develop from neural crest and neural ectoderm (e.g., small cell carcinoma of lung). Sarcomas, malignant tumors of connective tissue origin (e.g., fibrosarcoma), and teratomas are derived from all three germ cell layers (e.g., teratoma of the ovary or testis).


Malignant tumors are characterized by the following:



Biologically distinct and relatively rare populations of tumor-initiating cells have been identified in cancers of the hematopoietic system, brain, and breast. Cells of this type have the capacity for self-renewal, the potential to develop into any cell in the overall tumor population, and the proliferative ability to drive continued expansion of the population of malignant cells. The properties of these tumor-initiating cells closely parallel the three features that define normal stem cells. Malignant cells with these functional properties are termed cancer stem cells (Fig. 33-3). Cancer stem cells can be the source of all the malignant cells in a primary tumor.


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Figure 33-3 Stem cell systems.
Normal tissues arise from a central stem cell that grows and differentiates to create progenitor and mature cell populations. Key properties of normal stem cells are the ability to self-renew (curved arrow), multilineage potential, and extensive proliferative capacity. Cancer stem cells arise by means of mutation in normal stem cells or progenitor cells and subsequently grow and differentiate to create primary tumors (broken arrow indicates that specific types of progenitors involved in the generation of cancer stem cells are unclear). As with normal stem cells, cancer stem cells can self-renew, give rise to heterogeneous populations of daughter cells, and proliferate extensively. (Adapted from Jordan CT, Guzman ML, Noble M: N Engl J Med 355:1253-1260, 2006.)

Despite decreases in the incidence of some cancers and associated mortality, cancer remains highly lethal and very common. About 41% of Americans will develop some form of cancer, including nonmelanoma skin cancer, in their lifetime; 20% of Americans will die from cancer. Cancer is the second leading cause of death in the United States.



Epidemiology


Lung, colorectal, and breast cancers are the leading causes of cancer deaths in the United States. The types of cancer that have been increasing in incidence are cancer of the lung, breast, prostate, and pancreas and multiple myeloma, malignant melanoma, and Hodgkin’s lymphoma. The types of cancer that are decreasing in incidence are cancer of the stomach, cervix, and endometrium.





Risk Factors


Risk factors are important in specific cancers. Smoking is responsible for one third of cancers. Other risk factors include a high-fat, low-fiber diet, obesity, and a sedentary lifestyle. Certain types of cancer are more prevalent in specific populations. For example, U.S. blacks have a 20% greater prevalence of cancer than whites. The risk of breast cancer increases with age, and deaths are related to geography. Risk factors for breast cancer include family history, particularly breast cancer in a first-degree relative, first pregnancy after age 30 years, presence of fibrocystic disease, probably the use of oral contraceptives or hormone replacement therapy, prior breast or chest wall radiation, prior breast cancer, and ethanol consumption.


Survivors of childhood and adolescent cancer constitute one of the higher risk populations. The curative therapy (e.g., chemotherapy, radiation) administered for the cancer also affects growing and developing tissues. These patients are at increased risk for early mortality caused by second cancers and cardiac or pulmonary disease. Two thirds of survivors have at least one chronic or late-occurring health problem.



Causative Factors in Human Cancer


Factors that cause most neoplasms are unknown. They can be classified as environmental factors (e.g., chemical and radiation), host factors and disease associations, and viruses.



Environmental Factors


The incidence of cancer has been correlated with certain environmental factors. Table 33-1 lists environmental factors that have been definitively linked with cancer, including aerosol and industrial pollutants, drugs, and infectious agents. Radiation exposure is also known to be associated with specific types of cancer (e.g., acute leukemia, thyroid cancer, sarcomas, breast cancer). Women concerned about organochlorine substances (e.g., polychlorinated biphenyls [PCBs], dioxins, pesticides [DDT, banned in 1972]) can be reassured that available evidence does not suggest an association between exposure to these chemicals and breast cancer.



Most chemical carcinogens are inactive in their native state and must be activated by enzymes in the cytochrome P-450 or other enzyme systems (e.g., bacterial enzymes or enzymes induced by alcohol).


In radiation carcinogenesis, ionizing particles (e.g., alpha and beta particles, gamma rays, x-rays) hydrolyze water into free radicals, which are mutagenic to DNA by activating proto-oncogenes. Ultraviolet (UV) light, especially UVB, induces the formation of thymidine dimers, which distort the DNA molecule, leading to skin cancers (e.g., basal cell carcinoma, malignant melanoma).



Host Factors and Disease Associations


Various host factors have been linked to a higher than expected incidence of cancer. For example, the presence of certain genetic disorders (e.g., Down syndrome) is associated with an increased incidence of leukemia. The link between certain genetic abnormalities and leukemia is consistent with a germinal or somatic mutation in a stem cell line.


Familial clustering of germ cell tumors, malignant tumors arising in the testis, has been observed, particularly among siblings. Cryptorchidism and Klinefelter’s syndrome are predisposing factors in the development of germ cell tumors arising from the testis and mediastinum, respectively.


The incidence of cancer is 10,000 times greater than expected in patients with an immunodeficiency syndrome. The increased incidence of lymphomas in congenital, acquired, and drug-induced immunosuppression is consistent with the failure of normal immune mechanisms or antigen overstimulation with a loss of normal feedback control. Table 33-2 lists other cancer-related conditions.




Viruses


Viral causes of some cancers are known. Viruses associated with specific cancers are listed in Table 33-1. Nonpermissive cells that prevent an oncogenic RNA or DNA virus from completing its replication cycle often produce changes in the genome that result in the activation of proto-oncogenes or inactivation of suppressor genes.



Stages of Carcinogenesis


Some precancerous conditions progress through a series of growth alterations before becoming cancerous. For example, cervical cancer progresses from squamous metaplasia to squamous dysplasia to carcinoma in situ, and finally to invasive cancer. Endometrial cancer progresses from endometrial hyperplasia to atypical endometrial hyperplasia to carcinoma in situ, and finally to invasive cancer.


Cancer (Box 33-1) results from a series of genetic alterations that can include the following:



Box 33-1   The Process of Cancer


Cancer is a multistep process involving the following:




Mutation or overexpression of oncogenes produces proteins that can stimulate uncontrolled cell growth, whereas mutation or deletion of tumor suppressor genes results in the production of nonfunctional proteins that can no longer control cell proliferation. The mutant cell multiplies and the succeeding generations of cells aggregate to form a malignant tumor.


Interleukin-24 (IL-24), initially called MOB-5, is a protein that is usually secreted by immune system cells in response to injury or infection. Research on colon cancer cells has demonstrated that IL-24, in conjunction with its receptors, appears to give a cancer cell the ability to fuel its own growth. The secreted proteins are released from one cell to transmit a signal to grow, migrate, or survive to another cell. These proteins cannot act alone and must act through a receptor or receptors on the receiving cell.



Cancer-Predisposing Genes


Cancer-predisposing genes may act in the following ways:



Relatively few cancer-predisposing genes have been described. An absence of functional alleles at specific loci, however, allows the genesis of the malignant process (Table 33-3). For example, individuals with certain mutations in the gene BRCA2 are at a very high risk (up to 85%) for developing breast cancer and other cancers (e.g., ovarian cancer) because a DNA repair path cannot properly repair ongoing wear and tear to the DNA.



A mutation in a gene thought to be responsible for colon cancer may initially cause it. This gene, APC, normally limits the expression of a protein, survivin. When APC is altered, survivin works overtime and, instead of dying, stem cells in the colon overpopulate, resulting in cancer. Survivin is overexpressed in colon cancer. It prevents programmed cell death, or apoptosis, the process whereby cells normally die. Rather than dying on schedule, cancer cells instead grow out of control. The APC gene controls the amount of survivin by shutting down its production.



Proto-Oncogenes


Proto-oncogenes act as central regulators of the growth in normal cells that code for proteins involved in growth and repair processes in the body. Proteins such as growth factors or transcription factors are necessary for normal growth.


Genetic mutations in proto-oncogenes produce oncogenes. Oncogene activation causes the overexpression of growth-promoting proteins, resulting in hypercellular proliferation and tumorigenesis. Tumor suppressor genes normally counteract proto-oncogenes by encoding proteins that prevent cellular differentiation. When mutations in tumor suppressor genes cause loss of function, the expressed tumor suppressor proteins are no longer able to suppress cellular growth.


For example, the activation of proto-oncogenes (e.g., ras) involved in the growth process or inactivation of suppressor genes (e.g., p53), which keeps growth in check by binding and activating genes that put the brakes on cell division, is responsible for neoplastic transformation of a cell. Defects in the gene for p53 cause about 50% of all cancers.



p53 Protein


The p53 gene (tumor suppressor gene) is located on chromosome 17 and produces a protein that downregulates the cell cycle. A mutation of p53 is associated with an increased incidence of many types of cancer. The p53 tumor suppressor protein is dysfunctional in most human cancers. Even when p53 is not itself mutant, its regulators (e.g., p14ARF, a p53-stabilizing protein) are often altered. The p53 protein is a key responder to various stresses, including DNA damage, hypoxia, and cell cycle aberrations. Specific molecular pathways that activate p53 depend on the nature of the stress and the cell type. Consequently, these determine the specific downstream effectors and cellular response—apoptosis, growth arrest, or senescence.


It is widely believed that the central role of p53 in tumor suppression is to mediate the response to DNA damage. If p53 is missing when damage occurs, cells do not undergo p53-mediated arrest or apoptosis. Cells that have sustained mutations in oncogenes or tumor suppressor genes because of the damage obtain a growth advantage that fuels the development of cancer.


Apparently, DNA damage itself is not the critical event that leads to cancer, as long as the oncogenic stress pathways that activate p53 are intact. For any given cancer type, p53 dysfunction generally correlates with poor treatment response and poor prognosis; therefore, restoration of p53 function is a potential avenue for therapeutic development. Drugs currently being developed will enhance the function of kinases that activate p53 in response to DNA damage.



Role of Oncogenes


The genetic targets of carcinogens are oncogenes. Oncogenes have been associated with various tumor types (e.g., HER-2/neu with breast, kidney, and ovarian cancers). Oncogenes are considered altered versions of normal genes. Over a lifetime, a variety of mutations can convert a normal gene into a malignant oncogene.


Once an oncogene is activated by mutation, it promotes excessive or inappropriate cell proliferation. Oncogenes have been detected in about 15% to 20% of a variety of human tumors and appear to be responsible for specifying many of the malignant traits of these cells. More than 30 distinct oncogenes, some of which are associated with specific tumor types, have been identified (Table 33-4). Each gene has the ability to evoke many of the phenotypes characteristic of cancer cells.



Major classes of oncogene products involved in the normal growth process of cells include the following:



In addition, tumor suppressor genes (antioncogenes) are guardians of unregulated cell growth (e.g., p53, Rb oncogenes).



Mechanisms of Activation


Point mutations, translocations (e.g., t8;142 in Burkitt’s lymphoma) and gene amplification (multiple copies of the gene with overexpression of products) are mechanisms of activation, as follows:



• Overexpression of the c-erbB-2 (HER2/neu) oncogene is noted in up to 34% of patients with invasive ductal breast carcinoma and predicts poor survival.


• Activation of the ras proto-oncogene (point mutation) is associated with about 30% of all human cancers. About 25% of patients with acute myelogenous leukemia display this point mutation. Ras is mutated frequently in colon and pancreatic cancers; it appears that ras activation leads to unregulated expression of IL-24 and its receptors.


• Translocation of the abl proto-oncogene from chromosome 9 to chromosome 22 with formation of a large bcr-abl hybrid gene on chromosome 22 (Philadelphia chromosome) results in chronic myelogenous leukemia.


• Inactivation of suppressor genes (point mutations) leads to unrestricted cell division, inactivation of each of the RB1 suppressor genes on chromosome 13 is associated with malignant retinoblastoma in children, and inactivation of the p53 suppressor gene on chromosome 17 accounts for 25% to 50% of all malignancies involving the colon, breast, lung, and central nervous system.




Tumor-Suppressing Genes


A very different class of cancer genes has been discovered. These tumor-suppressing genes in normal cells appear to regulate the proliferation of cell growth. When this type of gene is inactivated, a block to proliferation is removed and cells begin a program of deregulated growth, or the genetically depleted cell itself may proliferate uncontrollably. Thus, tumor-suppressing genes are referred to as antioncogenes. In time, their discovery will lead to the reformulation of ideas about how the growth of normal cells is regulated.


Much speculation surrounds the operation of tumor-suppressing genes in normal tissue. It is known that normal cells exert a negative growth influence on each other within a tissue. Normal cells also secrete factors that are negative regulators of their own growth and that of adjacent cells. Diffusible factors may also be released by normal cells to induce the end-stage differentiation of other cells in the immediate environment; these factors include the following:



Normal gene products appear to prevent malignant transformation in some way. It is speculated that normal cells must have receptors that detect the presence of these growth-inhibiting and differentiation-inducing factors, which allow them to process the signals of negative growth and respond with appropriate modulation of growth. Genes may specify proteins necessary to detect and respond to the negative regulators of growth. If this process becomes dysfunctional as a result of inactivation or the absence of a critical component, such as the loss of chromosomal loci, a cell may continue to respond to mitogenic stimulation but lose its ability to respond to negative feedback to cease proliferation. Animal experiments have suggested that human beings carry a repertoire of genes, each of which is involved in the negative regulation of the growth of specific cell types. Somatic inactivation of these genes may be involved in the initiation of tumor cell growth or the transformation of benign tumors into malignant ones. Therefore, the somatic inactivation of tumor-suppressing genes may be as important to carcinogenesis as the somatic activation of oncogenes.



Body Defenses Against Cancer


Although there is no single satisfactory explanation for the success of tumors in escaping the immune rejection process, it is believed that early clones of neoplastic cells are eliminated by the immune response. The growth of malignant tumors is primarily determined by the proliferative capacity of the tumor cells and by the ability of these cells to invade host tissues and metastasize to distant sites. It is believed that malignant tumors can evade or overcome the mechanisms of host defenses (Color Plate 18).


Tumor immunity has the following general features:



Host defense mechanisms against tumors are both humoral and cellular. Effector mechanisms include the following:





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Jun 12, 2016 | Posted by in IMMUNOLOGY | Comments Off on Tumor Immunology

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