Human Immunity, Inflammation, and Cancer Biology Essentials

Body's Defense Systems: An Introduction

1. Know that innate (inborn) defenses are the first line of defense:
   • Present at birth.
   • Include the surface barriers, skin, and mucous membranes.
2. Inflammation is the second line of defense:
   • Activated with injury or infectious disease.
3. Adaptive (acquired) immunity is the third line of defense:
   • Is specific to particular antigens.
   • Has memory.

Innate Immunity Mechanisms

1. Neonates often have transiently depressed inflammatory function, particularly neutrophil chemotaxis and alternative complement pathway activity.
2. Elderly persons are at risk for impaired wound healing, usually because of chronic illnesses.
3. There are three layers of human defense:
   • Physiologic barriers.
   • The inflammatory response.
   • Adaptive (acquired) immunity.
4. Physical barriers are the first lines of defense, functioning to prevent damage to the individual and thwart the entrance of pathogens. These barriers include the skin and mucous membranes.
5. Antibacterial peptides are found in mucous secretions, perspiration, saliva, tears, and other secretions. They provide a biochemical barrier against pathogenic microorganisms.
6. The skin, mucous membranes, and the lining of the gastrointestinal (GI) tract are colonized by commensal or mutualistic microorganisms. These microorganisms provide protection by releasing biochemical compounds which facilitate immune responses and prevent colonization by pathogens. Within the gut, they also facilitate digestion in the GI tract.
7. The second line of defense is the inflammatory response, a rapid and nonspecific protective response to cellular injury resulting from any cause. It can occur only in vascularized tissues.
8. Know the macroscopic hallmarks of inflammation: redness, swelling, heat, pain, and loss of function for the inflamed tissues.
9. The microscopic hallmarks of inflammation are vasodilation, increased capillary permeability, and an accumulation of fluid and cells at the inflammatory site.
10. Inflammation is mediated by three key plasma protein systems: the complement system, the clotting system, and the kinin system. The components of all three systems are a series of inactive proteins which are activated sequentially in the presence of tissue injury.
11. Know there are three pathways for activating the complement system, which can be activated through antigen-antibody reactions or by other products, e.g., bacterial lipopolysaccharides:
    • The classical pathway activates the complement system through antigen–antibody reactions.
    • The lectin pathway.
    • The alternative pathway.
    • The lectin and alternative pathways do not require antibody activation to recruit phagocytes, activate mast cells, and destroy pathogens.
12. The most biologically potent products of the complement system are C3b (opsonin), C3a (anaphylatoxin), and C5a (anaphylatoxin, chemotactic factor).
13. Know the functions of the clotting system in injury and inflammation: stops bleeding, localizes microorganisms, and provides a meshwork for repair and healing.
14. Bradykinin is the most important product of the kinin system and causes vascular permeability, smooth muscle contraction, and pain.
15. Control of inflammation regulates inflammatory cells and enzymes and localizes the inflammatory response to the area of injury or infection.
16. Carboxypeptidase, histaminase, kinase, and C1 inhibitor are inactivating enzymes. The fibrinolytic system and plasmin facilitate clot degradation after bleeding is stopped.
17. Many different types of cells are involved in the inflammatory process, including mast cells, endothelial cells, platelets, phagocytes (neutrophils, eosinophils, monocytes and macrophages, dendritic cells), lymphocytes, and natural killer (NK) cells.
18. Most cells express plasma membrane pattern recognition receptors (PRRs) which recognize molecules produced by infectious microorganisms. These molecules include pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). Toll-like receptors (TLRs) are transmembrane receptors and nucleotide-binding-like receptors (NLR-like), and nucleotide oligomerization domain-like (NOD-like) receptors are cytoplasmic receptors. They are expressed by many inflammatory cells and recognize both PAMPs and DAMPs. Upon recognition, they promote the release of cytokines and inflammatory mediators, which, in turn, eliminate damaged cells and protect against invasion by microbes.
19. The cells of the innate immune system secrete many biochemical mediators (cytokines), which are responsible for activating other cells and regulating the inflammatory response. These cytokines include chemokines, interleukins, interferons, and other molecules.
20. Chemokines induce chemotaxis (attraction) of leukocytes, fibroblasts, and other cells to promote phagocytosis and wound healing.
21. Interleukins are produced primarily by lymphocytes and macrophages. They either promote or inhibit inflammation by activating the growth and differentiation of leukocytes, especially lymphocytes.
22. The most important proinflammatory interleukins are interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNFα). IL-6 and IL-10 downregulate the inflammatory response.
23. Interferons are produced by cells that are infected by viruses. Once released from infected cells, interferons can stimulate neighboring healthy cells to produce substances that prevent viral infection.
24. The most important activator of the inflammatory response is the mast cell, located in connective tissue near capillaries. Mast cells initiate inflammation by releasing biochemical mediators (histamine and chemotactic factors) from cytoplasmic granules. They also synthesize other mediators (prostaglandins, leukotrienes, and platelet-activating factor [PAF]) in response to stimuli. Basophils, found in blood, function in a manner that is similar to mast cells.
25. Histamine is the major vasoactive amine released from mast cells. It increases vascular permeability through dilation of capillaries and retraction of endothelial cells lining the capillaries.
26. The endothelial cells lining the circulatory system (vascular endothelium) regulate circulating components of the inflammatory system, maintaining normal blood flow. They function in this capacity by preventing spontaneous activation of platelets and other elements of the clotting system.
27. During inflammation, the endothelium expresses receptors that stimulate leukocytes to exit the vessel. The endothelium also retracts to allow fluid to pass into the tissues.
28. Platelets interact with the coagulation cascade to stop bleeding. They release mediators which facilitate and control inflammation.
29. The neutrophil, also known as polymorphonuclear neutrophil (PMN), the predominant phagocytic cell in early inflammation, exits the circulation, through retracted endothelial junctions, by diapedesis. On exiting, it moves to the inflammatory site by chemotaxis.
30. Eosinophils release products that control the inflammatory response, and they are the principal cells that destroy parasitic organisms.
31. The macrophage, the predominant cell in the late inflammatory response, is highly phagocytic. Additionally, it is responsive to cytokines, which promote wound healing.
32. Dendritic cells function as messengers between the innate and acquired (adaptive) immune systems. They process antigens at the site of inflammation and transport the antigen to lymph nodes and spleen, where they present these antigens to the resident T cells. The result of this process is the formation of antibodies.
33. Phagocytosis is a multistep cellular process, which usually results in the destruction of pathogens and foreign debris. The steps include recognition and attachment, engulfment, formation of a phagosome, formation of a phagolysosome, and eventual destruction of the pathogen or foreign debris. Phagocytic cells engulf microorganisms, enclosing them within phagocytic vacuoles (phagolysosomes). The vacuoles contain toxins (especially metabolites of oxygen) and/or enzymes that kill and digest the microorganisms.
34. Opsonins are molecules which enhance phagocytosis by coating the antigen. This activity results in a stronger attraction between the microorganism and the phagocyte (“marking” the organism). It also enhances the affinity with which the phagocyte binds to the microorganism. Examples include antibodies and the complement component C3b.

Acute and Chronic Inflammation

1. Acute inflammation is self-limiting and usually resolves within 8 to 10 days.
2. Local manifestations of inflammation include the classic signs of redness, heat, swelling, pain, and loss of function. They are the result of vascular changes associated with the inflammatory process, including vasodilation and increased capillary permeability.
3. The principal systemic effects of inflammation are fever, leukocytosis (increased levels of circulating leukocytes), and an increase in plasma proteins, primarily the acute-phase reactants, IL-1, and IL-6.
4. Chronic inflammation can be a continuation of acute inflammation that lasts 2 weeks or longer, or it can occur as a distinct process without significant preceding acute inflammation.
5. Chronic inflammation is characterized by a dense infiltration of lymphocytes and macrophages. Granuloma formation is a process wherein the body walls off and isolates infectious microorganisms. It serves to protect the body from further tissue damage.

Wound Healing Processes

1. Resolution (regeneration) is the return of tissue to nearly normal structure and function. Repair is healing by scar tissue formation.
2. Resolution occurs when little tissue has been lost or where the injured tissue is capable of regeneration. This type of healing is called healing by primary intention.
3. Tissues that have sustained extensive damage or tissue types that are incapable of regeneration heal by repair, a process which results in the formation of a scar. This process is called healing by secondary intention.
4. Resolution and repair occur in two separate phases. The reconstructive phase occurs when the wound begins to heal. The maturation phase occurs when the healed wound is remodeled. Cellular activity decreases and the blood vessels regress.
5. Dysfunctional wound healing can be secondary to ischemia, excessive bleeding, excessive fibrin deposition, predisposing disorders (e.g., diabetes mellitus), wound infection, inadequate nutrients, use of NSAIDs and steroids, or altered collagen synthesis.
6. Dehiscence is a disruption where the wound pulls apart at the suture line.
7. A contracture is a structural deformity caused by the excessive shortening of collagen in scar tissue.

Adaptive Immunity: A Detailed Look

1. Adaptive immunity is a state of protection, primarily against infectious agents, that differs from inflammation by being slower to develop, being more specific, and having memory that makes it much longer lived.
2. The adaptive immune response is most often initiated by cells of the innate system. These cells process and present portions of invading pathogens (i.e., antigens) to lymphocytes in peripheral lymphoid tissue.
3. The adaptive immune response is mediated by two different types of lymphocytes—B lymphocytes and T lymphocytes. Each has distinct functions. B cells are responsible for humoral immunity that is mediated by circulating antibodies, whereas T cells are responsible for cell-mediated immunity, in which they kill targets directly or stimulate the activity of other leukocytes.
4. Know that adaptive immunity can be either active or passive depending on whether immune response components originated in the host (active) or came from a donor (passive, e.g., receiving someone else’s antibodies).
5. B and T lymphocytes leaving the primary lymphoid organs are immunocompetent but have not been exposed to antigen, thus are naïve.
6. Clonal selection is initiated when exposure to an antigen occurs.

Antigens and Immunogens

1. Antigens are molecules that bind and react with components of the immune response, such as antibodies and receptors on B and T cells. Most antigens can induce an immune response, and these antigens are called immunogens.
2. All immunogens are antigens, but not all antigens are immunogens.
3. Some pathogens are successful because they mimic “self” antigens but avoid inducing an immune response.
4. Common antigens include infectious agents, allergens, chemical agents, and abnormal molecules on the surface of cells.
5. Large molecules, such as proteins, polysaccharides, and nucleic acids, are most immunogenic. Thus molecular size is an important factor for antigen immunogenicity.
6. Haptens are antigens too small to be immunogens by themselves but become immunogenic after combining with larger molecules.
7. The antigenic determinant, or epitope, is the precise chemical structure with which an antibody or B-cell/T-cell receptor (BCR/TCR) reacts.
8. Self-antigens are antigens on an individual’s own cells. The individual’s immune system does not normally recognize self-antigens as immunogenic, a condition known as tolerance.

Immune Response: B and T Cell Collaboration

1. The generation of clonal diversity results in production of B and T lymphocytes with receptors against millions of antigens that possibly will be encountered in an individual’s lifetime occurs in the fetus in the primary lymphoid organs: the thymus for T cells and portions of bone marrow for B cells.
2. The generation of clonal diversity is the differentiation of lymphoid stem cells into B and T lymphocytes. Lymphoid stem cells interact with stromal cells through a variety of adhesion factors. As the stem cell matures it develops a variety of surface markers or receptors, one of the earliest is interleukin-7 (IL-7) receptor. IL-7, produced by stromal cells is critical for driving differentiation and proliferation of the B cell.
3. The next stage in development is formation of the BCR. The role of the BCR is to recognize antigen and communicate that information to the cell’s nucleus.
4. The enormous repertoire of BCR specificities is made possible by rearrangement of existing deoxyribonucleic acid (DNA) during B-cell development in the primary lymphoid organs, a process called somatic recombination.
5. Somatic rearrangement of the antibody variable regions will frequently result in a BCR that recognizes the individual’s own antigens, which may result in attack on “self” antigens expressed on various tissue and organs. Many of these “autoreactive B cells” are eliminated in the bone marrow. Most of the developing B cells undergo apoptosis. This entire process is referred to as clonal deletion or central tolerance.
6. The process of T-cell proliferation and differentiation is similar to that for B cells. The primary lymphoid organ for T-cell development is the thymus. Lymphoid stem cells travel through the thymus, where thymic hormones and the cytokine IL-7 promote lymphoid stem cell division and the production of receptors. They exit the thymus as mature immunocompetent T cells with antigen-specific receptors on the cell surface.
7. TCR proceeds in a manner similar to BCR. Initially proteins called CD4 and CD8 are expressed on the developing cells. As the cell matures they retain either the CD4 molecule or the CD8 molecule but not both. Eventually CD4 cells develop into T-helper cells (Th cells) and CD8 cells become T-cytotoxic cells (Tc cells). Other mature T cells include T-regulatory cells (Treg cells) and memory cells.
8. The generation of clonal diversity concludes when immunocompetent T and B cells migrate from the primary lymphoid organs into the circulation and secondary lymphoid organs to await antigen.
9. The induction of an immune response, or clonal selection, begins when antigen enters the individual’s body.
10. Most antigens must first interact with antigen-presenting cells (APCs) (e.g., dendritic cells, macrophages, and B cells).
11. To induce an optimal cellular or humoral immune response, APCs must present antigens to Th cells. Antigen is processed in the APCs and presented on the cell surface by molecules of the major histocompatibility complex (MHC). The particular MHC molecule (class I or class II) that presents antigen determines which cell will respond to that antigen. Th cells require that the antigen be presented in a complex with MHC class II molecules. MHC class II molecules are found only on APCs. Tc cells require that the antigen be presented by MHC class I molecules.
12. The T cell sees the presented antigen through the TCR and accessory molecules: CD4 or CD8. CD4 is found on Th cells and reacts specifically with MHC class II. CD8 is found on Tc cells and reacts specifically with MHC class I.
13. Th cells consist of:
    • Th1 cells, which help Tc cells respond to antigen.
    • Th2 cells, which help B cells develop into plasma cells.
    • Th17 cells, which help activate macrophages.
14. Tc cells bind to and kill cellular targets, such as cells infected with viruses or cancer cells.
15. The natural killer (NK) cell has some characteristics of the Tc cells and is important for killing target cells in which viral infection or malignancy has resulted in the loss of cellular MHC molecules.

Humoral Immunity: Antibodies

1. The humoral immune response consists of molecules (antibodies) produced by B cells. B cells are lymphocytes.
2. Antibodies are plasma glycoproteins that can be classified by chemical structure and biologic activity as immunoglobulin G (IgG), IgM, IgA, IgE, or IgD. Know the characteristics of each of the immunoglobulin types. IgM is the FIRST antibody produced in response to infection. IgG is the only antibody that can cross the placenta.
3. A typical antibody molecule is constructed of two identical heavy chains and two identical light chains (either κ or λ) and has two Fab portions that bind antigen and an Fc portion that interacts with complement or receptors on cells.
4. The protective effects of antibodies may be direct through the action of antibody alone or indirect requiring activation of other components of the innate immune response.
5. IgE is a special class of antibody produced against environmental antigens that are the primary cause of common allergies. It also protects the individual from infection by large parasitic worms (helminths).
6. The secretory immune system protects the external surfaces of the body through secretion of antibodies in bodily secretions, such as tears, sweat, saliva, mucus, and breast milk. IgA is the dominant secretory immunoglobulin.

Cell-Mediated Immunity

1. Other effector T cells include Tc cells that attack and destroy cells expressing antigens from intracellular origins, Treg cells that suppress the immune response, and T lymphokine–producing cells that secrete cytokines that activate other cells.
2. Tc cells are responsible for cell-mediated destruction of abnormal cells, such as tumor cells or cells infected with viruses.
3. Attachment to a target cell activates multiple killing mechanisms through which the Tc cell induces the target cell to undergo apoptosis.
4. Two subsets of Th cells amplify inflammation:
   • Th1 cells, in addition to assisting Tc-cell clonal selection, secrete cytokines that activate M1 macrophages to increase phagocytic and microbial killing functions.
   • Th2 cells, in addition to assisting B-cell clonal selection, secrete cytokines that activate M2 macrophages for healing and repair of damaged tissue.
5. Th17 cells secrete a set of cytokines that recruit phagocytic cells to a site of inflammation. Th17-cell cytokines also activate epithelial cells to produce antimicrobial proteins in defense against certain bacterial and fungal pathogens.
6. Treg cells are a diverse group of T cells that control the immune response, usually suppressing the response and maintaining tolerance against self-antigens. Treg cells produce very high levels of immunosuppressive cytokines, which decrease Th1 and Th2 activity by suppressing antigen recognition and Th-cell proliferation.

Pediatric Considerations: Newborn Self-Defense

1. Neonates often have transiently depressed inflammatory function, particularly neutrophil chemotaxis and alternative complement pathway activity.
2. The T cell–independent immune response is adequate in the fetus and neonate, but the T cell–dependent immune response develops slowly during the first 6 months of life.
3. Maternal IgG antibodies are transported across the placenta into the fetal blood and protect the neonate for the first 6 months, after which they are replaced by the child’s own antibodies.

Geriatric Considerations: Elderly Self-Defense

1. Elderly persons are at risk for impaired wound healing, usually because of chronic illnesses.
2. T-cell function and antibody production are somewhat deficient in elderly persons. Elderly individuals also tend to have increased levels of circulating autoantibodies (antibodies against self-antigens).

Alterations in Immunity

Hypersensitivity Reactions

1. Hypersensitivity is an immune response misdirected against the host’s own tissues (autoimmunity) or directed against beneficial foreign tissues, such as transfusions or transplants (alloimmunity); or it can be exaggerated responses against environmental antigens (allergy).
2. Mechanisms of hypersensitivity are classified as:
   • Type I (immunoglobulin E [IgE]–mediated) reactions.
   • Type II (tissue-specific) reactions.
   • Type III (immune complex–mediated) reactions.
   • Type IV (cell-mediated) reactions.
3. Hypersensitivity reactions can be immediate (developing within seconds or hours) or delayed (developing within hours or days).
4. Anaphylaxis, the most rapid immediate hypersensitivity reaction, is an explosive reaction that occurs within minutes of reexposure to the antigen and can lead to shock.
5. Type I (IgE-mediated) reactions occur after antigen reacts with IgE on mast cells, leading to mast cell degranulation and the release of histamine and other inflammatory substances.
6. Type II (tissue-specific) reactions are caused by four possible mechanisms: complement-mediated lysis, opsonization and phagocytosis, antibody-dependent cell-mediated cytotoxicity, and modulation of cellular function.
7. Type III (immune complex–mediated) reactions are caused by the formation of immune complexes that are deposited in target tissues, where they activate the complement cascade, generating chemotactic fragments that attract neutrophils into the inflammatory site.
8. Immune complex disease can be a systemic reaction, such as serum sickness (e.g., Raynaud phenomenon), or localized, such as the Arthus reaction.
9. Type IV (cell-mediated) reactions are caused by specifically sensitized T cells, which either kill target cells directly or release lymphokines that activate other cells, such as macrophages.
10. Allergens are antigens that cause allergic responses, usually a type I hypersensitivity response.
11. Autoimmune disease is loss of tolerance to self-antigens. There can be a genetic predisposition, and the diseases can be a type II or type III hypersensitivity reaction.
12. Alloimmunity is the immune system’s reaction against antigens on the tissues of other members of the same species.
13. Alloimmune disorders include transient neonatal disease, in which the maternal immune system becomes sensitized against antigens expressed by the fetus; and transplant rejection and transfusion reactions, in which the immune system of the recipient of an organ transplant or blood transfusion reacts against foreign antigens on the donor’s cells.

Immunodeficiency Disorders

1. Immunodeficiency is the failure of mechanisms of self-defense to function in their normal capacity.
2. Immunodeficiencies are either primary or secondary. Congenital immunodeficiencies are caused by genetic defects that disrupt lymphocyte development, whereas acquired immunodeficiencies are secondary to disease or other physiologic alterations.
3. The clinical hallmark of immunodeficiency is a propensity to unusual or recurrent severe infections. The type of infection usually reflects the immune system defect.
4. The most common infections in individuals with defects of cell-mediated immune response are fungal and viral, whereas infections in individuals with defects of the humoral immune response or complement function are primarily bacterial.
5. Severe combined immunodeficiency (SCID) is a total lack of T-cell function and a severe (either partial or total) lack of B-cell function.
6. Wiskott-Aldrich syndrome (WAS) is caused by decreased production of IgM antibody.
7. DiGeorge syndrome is characterized by complete or partial lack of the thymus (resulting in depressed T-cell immunity), frequently associated with diminished or absent parathyroid gland activity (resulting in hypocalcemia) and cardiac anomalies.
8. Antibody deficiencies result from defects in B-cell maturation or function and range from a complete lack of the human bursal equivalent, the lymphoid organs required for B-cell maturation (as in Bruton agammaglobulinemia), to deficiencies in a single class of immunoglobulins (e.g., selective IgA deficiency).
9. Phagocyte defects include inadequate numbers or alteration in function, such as inadequate adhesion to bacteria or ineffective killing.
10. Complement and mannose-binding lectin deficiencies also are rare causes of increased risk for infection.
11. Primary immunodeficiency syndromes are usually treated with replacement therapy. Deficient antibody production is treated by replacement of missing immunoglobulins with commercial gammaglobulin preparations. Lymphocyte deficiencies are treated by the replacement of host lymphocytes with transplants of bone marrow, fetal liver, or fetal thymus from a donor. There are ongoing trials for gene therapy.
12. Acquired immunodeficiencies are caused by superimposed conditions, such as malnutrition, malignancy, medical therapies, physical or psychologic trauma, or infections.
13. Malignancy is associated with both local and generalized immune suppression that can result in life-threatening infections.
14. Treatments for hypersensitivity disorders, malignancy, and transplant rejection cause profound immune suppression and the benefits of these treatments must be carefully balanced with the risks.
15. Acquired immunodeficiency syndrome (AIDS) is acquired dysfunction of the immune system caused by a retrovirus (HIV) that infects and destroys T-helper cells.

Infection Biology

Microorganisms and Human Interaction

1. Infectious disease is a significant cause of morbidity and mortality in the United States and worldwide.
2. Pathogens have unique characteristics that influence their ability to overcome body defense mechanisms and cause disease.
3. The process of infection includes encounter and transmission, colonization, invasion, dissemination, and cellular or tissue damage by the pathogenic microorganisms.
4. Recognize the characteristics of each of the four distinct stages of infection: incubation period, prodromal stage, invasion or acute illness stage, and convalescence.

Infectious Disease Mechanisms

1. Recognize that bacteria have virulence factors that promote their ability to cause infection and cell injury, including pili, flagella, capsules, enzymes, competition for iron, and toxins.
2. Understand the difference between bacterial exotoxins and endotoxins. Exotoxins are enzymes produced by bacteria that can damage the plasma membranes of host cells or can inactivate enzymes critical to protein synthesis, and endotoxins activate the inflammatory response and produce fever.
3. Septicemia results from the proliferation of bacteria in blood. Toxins released by bloodborne bacteria cause the release of vasoactive enzymes that increase the permeability of blood vessels. Leakage from vessels causes hypotension that can result in septic shock.
4. Viruses are intracellular parasites. They enter host cells and use their metabolic processes to proliferate and cause disease.
5. Viruses that have invaded host cells may decrease protein synthesis; disrupt lysosomal membranes; form inclusion bodies, where synthesis of viral nucleic acids is occurring; fuse with host cells to produce giant cells; alter antigenic properties of the host cell; transform host cells into cancerous cells; and promote bacterial infection.
6. Viruses can elude the immune system by making small changes to the genes that produce viral surface antigens, a process known as antigenic variation.
7. Diseases caused by fungi are called mycoses, and fungi occur in two forms: yeasts (spheres) and molds (filaments or hyphae).
8. Dermatophytes are fungi that infect skin, hair, and nails with diseases, such as ringworm and athlete’s foot.
9. Candida albicans is the most common cause of fungal infections in humans.
10. Parasitic microorganisms range from unicellular protozoa to large worms. Although less common in the United States, parasites and protozoa are common causes of infection worldwide.
11. Parasitic and protozoal infections are rarely transmitted from human to human. Infection mainly spreads through vectors (e.g., through mosquito bites) or through contaminated water or food (i.e., malaria, Chagas disease, sleeping sickness, and leishmaniasis).

Antibiotic Resistance

1. Pathogens can use various mechanisms to resist the effects of antibiotics, including transmission of resistance genes to new generations of bacteria, enzyme degradation of the antibiotic, ejection of the antibiotic from the pathogen, modification of the cell wall to prevent binding or uptake of the antibiotic, or modification of the target of the antibiotic.

Vaccines and Immune Protection

1. Vaccines are biologic preparations of antigens that, when administered, stimulate production of protective antibodies or cellular immunity against a specific pathogen.
2. Passive immunotherapy is the administration of preformed antibodies for protection against a specific pathogen, such as hepatitis A and B or rabies.

Cancer Biology Fundamentals

Cancer Terminology and Features

1. Cancer is a disease in which abnormal cells divide uncontrollably and invade other tissues. A tumor is a new growth, or neoplasm.
2. Know characteristics of benign tumors: they are usually encapsulated, well differentiated, with well-organized stroma and do not spread to distant locations. They are named for the tissues from which they arise. Benign tumors are noncancerous.
3. Malignant tumors are cancerous. Compared with benign tumors, malignant tumors have more rapid growth rates, specific microscopic alterations (anaplasia, or loss of differentiation, and pleomorphism, or variability in size and shape), absence of normal tissue organization, and no capsule. They invade blood vessels and lymphatics and have distant metastases. The stroma is disorganized with loss of normal tissue structure.
4. Cancers are named for the cell type from which they originate:
   • Carcinomas arise from epithelial tissue.
   • Lymphomas are cancers of lymphatic tissue.
   • Leukemias are cancers of blood-forming cells.
5. Carcinoma in situ (CIS) refers to noninvasive epithelial tumors of glandular or squamous cell origin. These early–stage cancers are localized to the epithelium and have not penetrated the local basement membrane.

Cellular Mechanisms of Cancer

1. Cancer is a complex disease and the microenvironment of a tumor is a heterogenous mixture of cells, both cancerous and benign.
2. Tumor initiation is dependent on mutational and epigenetic changes and characteristics of the microenvironment. Tumor progression is governed further by more genetic mutations, epigenetic alterations, and changing microenvironment.
3. Genetic changes include small and large DNA mutations that alter genes, chromosomes, and non–coding RNAs, as well as epigenetic changes because of altered chemical modifications of DNA and histones.
4. Driver mutations “drive” the progression of cancer. Passenger mutations are random events that do not contribute to the malignant phenotype. After a critical number of driver mutations, the cell becomes cancerous.
5. Mutations activate growth-promotion pathways, block antigrowth signals, prevent apoptosis, stimulate telomerase and new blood vessel growth, and allow tissue invasion and distant metastasis.
6. The processes that occur during the development of cancer are analogous to wound healing. The proliferation of cancer cells and enlargement of the tumor elicit synthesis of proinflammatory mediators by the cancer cells and adjacent nonmalignant cells.
7. Like wound healing, mediators recruit inflammatory/immune cells and cells normally associated with tissue repair. These cells form the stroma (tumor microenvironment) that surrounds and infiltrates the tumor.
8. Cancer heterogeneity or diversity arises from ongoing proliferation and mutation.
9. Hallmarks of cancer that are primarily genomic alterations include sustained proliferative signaling, evading growth suppression, genomic instability, and replicative immortality. Other hallmarks secondary to genomic change include induction of angiogenesis, reprogramming energy metabolism, resistance to destruction, and activating invasion and metastasis.
10. Normal cells only enter proliferative phases in response to growth factors. Cancerous cells characteristically express mutated or overexpressed proto-oncogenes, referred to as oncogenes, which are independent of normal regulatory mechanisms and signal uncontrolled sustained proliferation.
11. Some oncogenes, such as RAS, result from point mutations. Other oncogenes can result from genetic translocations. Translocation can cause excess and inappropriate production of a proliferation factor, such as with Burkitt lymphoma. Translocations can also lead to production of novel proteins with growth-promoting properties, as is seen with the Philadelphia chromosome in chronic myeloid leukemias (CML).
12. Tumor-suppressor genes normally regulate cell cycle, but they must be inactivated in cancer cells by mutations to each allele, one from each parent.
13. A common mutation in cancer cells is inactivation of the tumor suppressor gene tumor protein p53 (TP53), which activates caretaker genes, ones responsible for maintaining genomic integrity. Caretaker genes control expression of many genes that repair DNA damage, suppress cellular proliferation during genomic repair, and initiate apoptosis. Inactivation of p53 results in increased mutation rates and cancer.
14. In rare families, a germ cell mutation (an inheritable mutation on a sperm or egg cell) in a tumor-suppressor gene, such as TP53 or the retinoblastoma gene (RB), may lead to a greatly increased risk for developing particular cancers.
15. Genomic instability refers to an increased tendency of alterations/mutations in the genome during the life cycle of cells. Genomic instability may result from increased epigenetic silencing or modulation of gene function.
16. Changes in gene regulation can affect entire networks of signaling, not just single genes. Gene expression networks can be regulated by changes in microRNAs (miRNAs or miRs) and other non–coding RNAs (ncRNAs).
17. Cancer cells are immortal. When they reach a critical age, cancer cells activate telomerase to restore and maintain their telomeres, thereby allowing cancer cells to divide repeatedly or become immortal.
18. Like many normal adult tissues, cancers can contain rare stem cells that provide a source of immortal cells. To fully eradicate a cancer, it may be necessary to target the cancer stem cell.
19. Access to the vascular system is essential for tumor growth. Cancerous tumors maintain secretion of angiogenic factors and prevent the release of angiogenic inhibitors, which stimulates new blood vessel growth (called neovascularization or angiogenesis).
20. The vessels formed within tumors originate from endothelial sprouting from existing capillaries and irregular branching, rather than regular branching seen in healthy tissue. The vessels are also more porous and prone to hemorrhage and allow passage of tumor cells into the vascular system.
21. Cancer cells are able to reprogram energy metabolism. The successful cancer cell divides rapidly, with the consequent requirement for the building blocks of new cells, such as ATP. Many cancer genes encourage aerobic glycolysis instead of oxidative phosphorylation, which allows for a more efficient production of molecular building blocks needed for rapid growth.
22. Oncogenes can drive metabolic reprogramming, enabling cancer cells to (1) maintain deregulated proliferation, (2) withstand challenges associated with oxygen and nutrient limitations, (3) maintain a dedifferentiated state with associated alterations in gene expression, and (4) corrupt the surrounding microenvironment to assist tumor growth and dissemination.
23. In cancer, defects in the intrinsic or extrinsic cell death pathways, or both, provide resistance to apoptotic cell death.
24. Some conditions of chronic inflammation increase the risk of developing cancer. A prime example is the association between gastric cancer and infection with Helicobacter pylori.
25. The inflammatory response may contribute to the onset of cancer and be manipulated throughout the process to benefit tumor progression and spread.
26. One of the key cells that promote tumor survival is the tumor-associated macrophage (TAM). Most tumors have large numbers of TAMs, whose presence may correlate with a worse prognosis. Cancer-associated fibroblasts contribute greatly to cancer progression, local spread, and metastasis.
27. Unique antigens and other markers on tumor cells can be recognized by T cells and NK cells of the immune system, leading to destruction of the tumor cell.
28. The immune surveillance hypothesis predicts that most developing malignancies are suppressed by an efficient immune response against tumor-associated antigens. Therefore the rationale for immunotherapy predicts that the immune system could be used to target tumor-associated antigens and destroy tumors clinically.
29. The role of the immune system in protecting against cancer has been clearly documented against oncogenic viruses. Antibodies induced by vaccines against oncogenic viruses, such as human papillomavirus (HPV) and hepatitis B virus (HBV), protect against initial infection and development of cervical and liver tumors, respectively.
30. Cancer cells can evade rejection by the immune system by production of immunosuppressive factors, induction of immunosuppressive T-regulator cells, evolution of tumor-antigen negative variants, or suppressed expression of antigen-presenting MHC class I molecules.
31. Metastasis is the spread of cancer cells from the site of the original tumor to distant tissues and organs through the body and is the major cause of death from cancer.
32. Metastasis is a complex process that requires cells to have many new abilities, including the ability to invade, survive, and proliferate in a new environment.
33. Carcinomas undergo a process of epithelial-mesenchymal transition (EMT) during which many epithelial-like characteristics are lost (e.g., polarity, adhesion to basement membrane), resulting in increased migratory capacity, increased resistance to apoptosis, and a dedifferentiated stem cell–like state that favors growth in foreign microenvironments and establishment of metastatic disease.
34. Invasion, or local spread, consists of loss of cell-to-cell contact, degradation of the extracellular matrix (ECM), and increased motility of individual cancer cells. Stromal cells, particularly tumor-associated macrophages (TAMs), are essential to this process.
35. Some cancers appear to selectively home to particular metastatic sites, which may be a result of interactions between the cancer cells and specific receptors on the small blood vessels in different organs.

Clinical Manifestations of Cancer

1. Paraneoplastic syndromes are rare symptom complexes, often caused by biologically active substances released from a tumor or by an immune response triggered by a tumor, that manifest as symptoms not directly caused by the local effects of the cancer.
2. Common side effects of cancer and cancer therapy include anemia, bone density loss, cachexia, cardiac and pulmonary damage, fatigue, gastrointestinal issues, hair loss and skin conditions, infection, infertility, leukopenia and thrombocytopenia, lymphedema, and pain.
3. Anemia associated with cancer usually occurs because of malnutrition, chronic bleeding and resultant iron deficiency, chemotherapy, radiation, and malignancies in the blood-forming organs.
4. Cachexia is a multiorgan energy wasting syndrome where energy intake is decreased and energy expenditure is increased. Two factors are most significant: muscle loss and inflammation. Cachexia has many clinical manifestations including anorexia, early satiety (filling), weight loss, anemia, asthenia (marked weakness), taste alterations, and altered protein, lipid, and carbohydrate metabolism. Muscle wasting involves many protein signaling pathways and inflammatory mediators. Profoundly altered are both appetite-stimulating and appetite-suppressing brain pathways.
5. Fatigue is the most frequently reported symptom of cancer and cancer treatment.
6. The gastrointestinal tract relies on rapidly growing cells to provide an absorptive surface for nutrients. Both chemotherapy and radiation therapy may cause decreased cell turnover, thereby leading to oral ulcers (stomatitis), malabsorption, and diarrhea.
7. Alopecia (hair loss) results from chemotherapy effects on hair follicles. Alopecia is usually temporary, although hair may initially regrow with a different texture. Not all chemotherapeutic agents cause alopecia. Decreased renewal rates of the epidermal layers in the skin may lead to skin breakdown and dryness, altering the normal barrier protection against infection.
8. Infection is the most significant cause of complications and death. Immune suppression, lymphopenia, and granulocytopenia may result from the underlying cancer or secondary to treatment increasing the risk of serious microbial infections.
9. Leukopenia and thrombocytopenia are usually a result of chemotherapy (which is toxic to bone marrow) or radiation (which kills circulating leukocytes). Thrombocytopenia is a major cause of hemorrhage in people with cancer.
10. Pain is generally associated with the late stages of cancer. It can be caused by pressure, obstruction, invasion of a structure sensitive to pain, stretching, tissue destruction, and inflammation.

Cancer Diagnosis and Staging

1. The diagnosis of cancer requires a biopsy and examination of tumor tissue by a pathologist. Cancer classification is established by a variety of tests.
2. Tumor staging involves the size of the tumor, the degree to which it has locally invaded, and the extent to which it has spread. A standard scheme for staging is the T (tumor spread), N (node involvement), and M (metastasis) system.
3. Tumor markers are substances (i.e., hormones, enzymes, genes, antigens, antibodies) found in cancer cells and in blood, spinal fluid, or urine. They are used to screen and identify individuals at high risk for cancer, to help diagnose specific types of tumors, and to follow the clinical course of cancer. To date, no tumor marker has proven satisfactory to screen populations of healthy individuals for cancer.
4. The classification, and hence the treatment decisions, of cancers was originally based on gross and light microscopic appearance, and is now commonly accompanied by immunohistochemical analysis of protein expression. Increasingly, this is supplemented by a more extensive molecular analysis of the tumors.
5. Cancer is treated routinely with surgery, radiation therapy, chemotherapy, and combinations of these modalities. However, cancer therapy is rapidly evolving, and genetic analysis may help determine appropriate therapies.
6. Surgical therapy is used for nonmetastatic disease (in which cure is possible by removing the tumor) and as a palliative measure to alleviate symptoms.
7. Ionizing radiation causes cell damage; therefore the goal of radiation therapy is to damage the tumor without causing excessive toxicity or damage to nondiseased structures.
8. The theoretic basis of chemotherapy is the vulnerability of tumor cells in various stages of the cell cycle. Modern chemotherapy uses combinations of drugs with different targets and different toxicities.
9. Induction chemotherapy seeks to cause shrinkage or disappearance of tumors. Adjuvant chemotherapy is given after surgical excision of a cancer with the goal of eliminating micrometastases. Neoadjuvant chemotherapy is given before localized (surgical or radiation) treatment of a cancer to shrink a cancer so that surgery may spare more normal tissue.
10. Immunotherapy attempts to modify the immune system from a cancer-protective state to a destructive condition.
11. Future treatment of tumors will, most likely, use a careful histologic and genetic analysis of individual cancers that prescribes a combination of tumor-targeting drugs to simultaneously disrupt multiple hallmarks of that particular cancer.

Cancer Epidemiology and Risk Factors

Genetics, Epigenetics, and Tissue Environment

1. Cancer arises from a complicated and interacting web of multiple etiologies. Avoiding high-risk behaviors and exposure to individual carcinogens will prevent many types of cancers.
2. Risk factors for cancer include lifestyle behaviors (smoking, alcohol intake, diet), lack of physical exercise and obesity, certain infections, environmental factors (exposure to sunlight or ionizing radiation), occupational exposure to carcinogens, and certain medications.
3. Cancers are caused by environmental-lifestyle factors and genetic/epigenetic factors. Interacting factors are weaker immune systems, variations in detoxifying enzymes or DNA repair genes, differences in hormone levels, and metabolic factors. Altogether the biologic environment is modified by metabolic and hormonal factors, inflammation, and disordered glucose and lipid metabolism.
4. Cancer-causing factors are influenced by the surrounding microenvironment or stroma. Once malignant phenotypes have developed, complex interactions occur between the tumor, the surrounding stroma, and the cells of the immune and inflammatory systems.
5. Globally cancer is reported to become a major cause of morbidity and mortality in the coming decades.
6. In the United States, cancer incidence rates decreased for men and stayed about the same for women from 2003 to 2012. During this same time period, cancer incidence rates increased in children 0 to 19 years of age.
7. Overall, cancer death rates have continued to decline in men, women, and children. However, deaths caused by liver cancer increased at the highest rate of all reported cancer sites, and liver cancer incidence rates increased sharply.

Early Life Influences on Cancer Risk

1. Emerging data suggest early life events influence later susceptibility to chronic diseases.
2. Developmental plasticity is the degree to which an organism’s development is contingent on its environment. Plasticity refers to the ability of genes to organize physiologically or structurally in response to environmental conditions during fetal development. Be familiar with studies on in utero exposure to DES and the effect on female reproductive system cancers later in life.
3. The developmental origins’ hypothesis suggests that nutrition and other environmental factors affect cellular pathways during gestation, enabling a single genotype to produce a broad range of adult phenotypes. Maternal nutrition, as well as environment factors, are proposed as significant biological influences.
4. Undernutrition in utero is linked to increased heart disease, metabolic disorders, and possibly breast cancer decades later. Early versus late undernutrition in pregnancy indicated that the first trimester of pregnancy is particularly vulnerable to disease outcome in adulthood.

Environmental and Lifestyle Factors: Tobacco

1. Cigarette smoking is carcinogenic and the most important cause of cancer. Tobacco smoking causes cancer in more than 15 organ sites, and exposure to secondhand smoke and parental smoking causes cancer in children and in other nonsmokers. The risk is greatest in those who begin to smoke when young and continue throughout life. Smoking is, however, pandemic affecting all ages.
2. Worldwide, tobacco use causes more than 7 million deaths per year.
3. Environmental tobacco smoke (i.e., secondhand smoke) is a cause of stroke; increases the risk of death in people with cancer and cancer survivors as well as those with macular degeneration, tuberculosis, ectopic pregnancy, and diabetes mellitus. Secondhand smoke exposure increases inflammation, impairs immunity, and is a cause of rheumatoid arthritis.
4. Smoking tobacco is linked to cancers of the lung, upper aerodigestive tract, stomach, lower urinary tract, kidney, pancreas, cervix, uterus, and myeloid leukemia. Recently added to the list are liver cancer and colorectal cancer. Smoking causes even more deaths from respiratory, vascular, and other diseases than from cancer.
5. Cigar or pipe smoking is related to cancers of the oral cavity, oropharynx, hypopharynx, larynx, esophagus, and lung. Pipe smokers have an increased risk of cancers of lung, lip, throat, esophagus, larynx, pancreas, and colon and rectum.
6. Electronic cigarettes can contain harmful and potentially cancer causing substances.

Dietary Impact on Cancer Risk

1. The influence of diet on cancer development is complicated. Cancer risks in older adults may depend as much on diet in early life as on current eating practices.
2. Nutrigenomics is the study of the effects of nutrition on the phenotypic variability of individuals based on genomic differences.
3. Nutrition, Obesity, Alcohol Consumption, and Physical Activity: Impacts on Cancer - Diet, weight, and activity level all influence risks for cancer development.
4. The implementation of dietary patterns, for example, the Mediterranean dietary pattern, and the promoting of specific dietary recommendations, is becoming more widespread.
5. The importance of diet has been illustrated by data showing changes in cancer risk among migrants in low-risk countries compared with those in high-risk countries. With geographic migration, risks and cancer patterns change, particularly with the adoption of the Western diet.
6. Bioactive components have a profound effect on differentiation, potentially including differentiation of cancer stem cells. Intake of specific food compounds may suppress cancer stem renewal.
7. A variety of food compounds may influence DNA repair.
8. Xenobiotics are toxic, mutagenic, and carcinogenic chemicals that humans are constantly exposed to. The body has defense systems for counteracting these effects. Many foods enhance the efficiency and degree of detoxification of xenobiotics and thus serve a protective role in metabolizing carcinogens.
9. Diets high in red meat or processed meat may lead to increased risks of development colorectal cancer. Meats containing nitrites, nitrates, or other preservatives can leave residues in the colon that cause DNA damage.